Lymph Node

Lymph nodes are kidney-shaped secondary lymphoid organs (normal size from <
1mm to 2 cm depending on the region of the body and presence or absence of
infection or neoplastic process) with 2 primary functions:
o 1) For pathologic processes, macrophages within the node trap viruses,
bacteria, fungi, debris (e.g. anthracotic pigment), and malignant cells
o

2) During reactive processes, lymph nodes store lymphocytes and

macrophages that proliferate secondary to a nearby pathologic process

Structure:
o

Surrounded by a fibrous capsule that extends centrally to form trabeculae

The substance of the lymph node is divided into an outer cortex and the
inner medulla

The only location where the medulla is exposed (at the surface of the lymph
node) is at the hilum

Cortex: composed of lymphoid follicles (mainly contain B-cells within a loose

network of antigen-presenting follicular dendritic cells) as well as reticular cells,
macrophages, and some scattered CD4 helper T cells.
o

Prior to antigenic stimulation, these are primary follicles primarily

composed of small, resting B cells

In response to antigenic stimulation, secondary follicles form. These

contain a pale germinal center (mainly activated, proliferating B cells) and a
mantle zone (both antigen-presenting B cells and T helper cells)

Paracortex: border between the cortex and the medulla. This is the main repository
of T cells within lymph nodes.
o

T and B cells enter through high endothelial venules (HEVs)

This is where antigen is presented (by APCs) to T helper cells and some B
cells. These stimulated B and T cells travel to the cortex to activate the
primary follicles

Swells with lymphocytes during infections

Will be much smaller in any patient with acquired or congenital athymia

(e.g. DiGeorge syndrome).

Medulla: consists of large blood vessels, medullary cords, and medullary sinuses
o

Medullary cords are rich with antibody-producing plasma cells

These antibodies exit the lymph node via cortical sinuses, which drain into
the medullary sinuses, then into the efferent lymphatics

Medullary sinuses are endothelial-lined lymphatic spaces that collect lymph

destined for the efferent lymphatics. They contain macrophages and reticular
cells.

Key Lymphatic Drainages

o

Deep lymphatics of the arm and the pectoral region axillary nodes

Stomach peri-gastric and gastro-omental nodes celiac lymph nodes

Duodenum pancreaticoduodenal and pyloric lymph nodes. Jejunum,

ileum, right colon, and transverse colon superior mesenteric nodes

Descending and sigmoid colon inferior mesenteric lymph nodes. The

splenic flexure can drain to both the superior and inferior mesenteric nodes

Inferior rectum and anal canal above the pectinate line internal iliac
nodes

Anal canal below the pectinate line superficial inguinal nodes

Posterior abdominal wall, kidneys, testes or ovaries, and uterus paraaortic and para-caval nodes

Scrotum superficial inguinal nodes

Superficial thigh superficial inguinal nodes

Lateral dorsal foot popliteal nodes

The right lymphatic duct drains the right arm and the right half of the head

The thoracic duct begins anterior to L1 or L2 adjacent to the aorta.

It starts by draining the main abdominal lymphatic ducts, all of which empty
into the thoracic duct by the level of T12.
The thoracic duct passes through the diaphragm into the posterior
mediastinum, where it continues to collect drainage mainly from the left
upper quadrant of the body.
Then it empties into the venous system at the left venous angle (juncture of
the left subclavian and internal jugular veins)

Lymphoid Organs

Spleen
o

Secondary lymphoid organ. Location of immune response against bloodborne (not lymph-borne) antigens. Lymphatic vessels do not drain into the
spleen.

Consists of red pulp and white pulp separated by a diffuse marginal zone.

Spleens Red Pulp

o

The red pulp consists of sinuses and sinusoids that filter blood.

The sinusoids are lined by long, discontinuous layer of endothelial cells

there are large spaces between the endothelial cells

Many antigen-presenting cells (APCs), notably macrophages, are found in

the sinuses and sinusoids. Micro-organisms in the blood are cleared here,
importantly encapsulated organisms (e.g. pneumococcus) due to the spleens
role in manufacturing key components of the complement cascade

The red pulp is also the site where old and damaged RBCs are removed from
circulation

The splenic sinusoids in the red pulp are connected by the splenic cords of
Billroth, which contain macrophages, plasma cells, neutrophils,
erythrocytes, lymphocytes, and reticular cells

Spleens White Pulp (aka Malpighian corpuscles)

Contains the secondary lymphoid tissue of the spleen (compare to lymph

nodes)

White pulp tissues are organized around the spleens arterial supply. The
most central portion is PALS (the periarteriolar lymphatic sheath). Outside
PALS are lymphoid follicles

PALS predominantly contain T cells and dendritic cells. The dendritic cells
serve as APCs to the T cells

Lymphoid follicles mainly contain B cells: B cells entering the spleen from
the arterial system pass through PALS to the lymphoid follicle

From the white pulp, both B and T cells exit the spleen by traveling through
the red pulp to the splenic vein

Thymus
o

Functions to convert hematopoietic progenitor cells immature thymocytes

T-cells

The entire organ is enclosed by an investing capsule. Just deep to the capsule
is the cortex. The medulla is the thymic center.

Formed by fusion of the ventral wings of the third branchial pouch

Cortex: dense with immature T-cells

Medulla: pale-colored because it contains mature T-cells, epithelial reticular

cells, and Hassalls corpuscles (remains of epithelial tubes which grow out
from the third branchial pouches)

Corticomedullary junction: the site of both positive selection (selecting

functional T-cells) and negative selection (elimination of autoreactive T
cells)

Positive selection induces apoptosis of cells that bind too weakly while
negative selection induces apoptosis of cells that bind too strongly. Cells
with high-medium binding survive. Binding refers to the ability of the T-cell
receptors to bind to either MHC class I/II or peptide molecules.

Spleen

Thymus

Lymphocytes

Innate Immunity
o Innate immunity includes many cellular and humoral devices, from
nonspecific barriers (eg, skin) to recognition and destruction of specific
pathogens (eg, complement-mediated opsonization of microorganisms for
subsequent phagocytosis)
o

Innate immunity is maintained by a vast repertoire of serum proteins that

recognize general classes of invading agents and which constantly sample
the local environment. This provides for a fast immune response; however
the proteins do not exhibit any memory in the case of recurrent infection

The innate immune system includes natural killer cells, phagocytes,

neutrophils, dendritic cells, and complement

Adaptive Immunity
o

Involves memory: T and B cell receptors undergo somatic rearrangement

(VDJ recombination) which are produced long after infection

Response to infection is initially slow (often occurring after the innate

response). Response is faster upon repeat infection

Primarily involves T-cells, B-cells and circulating antibodies

Differentiation of T cells
o

All T cells originate from hematopoietic stem cells in the bone marrow

The earliest thymocytes found in the thymus are CD4-CD8- then

CD4+CD8+ thymocytes finally develop into either:
- CD4+CD8-, also known simply as CD4+ helper T cells, or Th cells; or
- CD4-CD8+, also known simply as CD8+ cytotoxic T cells, or CTLs.

Note: only 1-2 percent of T cells leave the thymus; most of the remaining T
cells apoptose

CD8+ T cells develop into cytotoxic cells (found in the lymph node) which
destroy viral-infected cells and tumor cells

CD4+ T cells develop into helper T cells in the thymusTh1 cells and Th2
cells:
- Th1 cells coordinate a CMI (cell-mediated immune) response and inhibit a
Th2-stimulated humoral response.
- Conversely, Th2 cells coordinate a humoral immune response and suppress
a Th1-stimulated CMI response

Th1 cells coordinate a cell-mediated immune response to eradicate

intracellular pathogens (eg, Listeria, myobacteria, Leishmania):
1. Intracellular pathogens stimulate a strong innate immune response
involving macrophages and NK cells differentiation of pleuripotent Th0
cells into Th1 cells is driven by IL-12 produced by macrophages and IFN-
produced by NK cells.
2. Th1 cells secrete IL-2, IFN-, TNF-, and TNF-
3. IFN- produced by Th1 cells promotes further development of Th1 cells.
4. Proliferation of Th1 cells is inhibited by IL-4 and IL-10 produced by Th2
cells.

Th2 cells coordinate a humoral (antibody) response to extracellular

pathogens (eg, helminths) and allergens:
1. Extracellular pathogens and allergens do not stimulate a strong innate
immune response involving macrophages and NK cells differentiation of
pleuripotent Th0 cells into Th2 cells is the default pathway and is driven by
constitutive elaboration of IL-4 by the naive Th0 cells themselves

2. Th2 cells secrete IL-4, IL-5, IL-6, IL-10, IL-13, and TGF
3. IL-4 and IL-10 produced by Th2 cells promote further development of
Th2 cells.
4. Proliferation of Th2 cells is inhibited by IFN- produced by Th1 cells.
[1]

Th2 cells help B cells make antibodies:

- Th2 cells are essential for IgE production
- Th2 cells also help stimulate production of IgG and IgA

HLA & MHC

HLA: Human Leukocyte Antigen Classes

Consists of three classes of molecules (Major Histocompatibility I, II, and

III)

Discriminates between self and nonself. Also involved in antigen

presentation to T cells by self-MHC restriction (antigens can only be
presented to T cells with the same HLA type).

Specific HLAs are associated with various immunologic disorders and

susceptibility to infectious agents

Major Histocompatibility Complex-I (MHC-I)

o

Expressed on virtually all cells

Encoded by the following Human Leukocyte Antigen (HLA) genes: HLAA, HLA-B, HLA-C

Antigens created from intracellular (cytoplasmic) peptides are loaded in the

rough endoplasmic reticulum. External Flash animation

MHC-I-dependent antigen presentation is the primary way for a virusinfected cell to activate T cells

Th1 cells activate macrophages and CD8+ T cells

2 microglobulin is necessary for cell surface expression of MHC-I. Note:

2 microglobulin is not expressed on RBCs

MHC-I molecules interact with CD8+ (cytotoxic) T cells

Major Histocompatibility Complex-II (MHC-II)

o

Primarily found on cell membranes of APCs (antigen presenting cells):

dendritic cells, macrophages, activated B cells. Also found on activated T
cells.

Encoded by the following Human Leukocyte Antigen (HLA) genes: HLADR, HLA-DP, HLA-DQ

Phagocytosed antigens are digested and loaded onto MHC-II from acidified
endosomes. External Flash animation

Major Histocompatibility Complex-III (MHC-III)

o

The function of the MHC-III region differs from MHC-I & MHC-II: the
MHC-III region encodes for complement (e.g. C2, C4) and tumor necrosis
factors (e.g. TNF-)

This region also encodes for 21-hydroxylase, a key enzyme in

glucocorticoid synthesis

B cells

Although B-cells and T-cells both originate in the bone marrow from lymphoid stem
cells, T-cells mature in the thymus whereas B-cells mature in the bone marrow:
Lymphoid stem cell pro-B cell (progenitor) pre-B cell (cytoplasmic +)
immature B cell (surface IgM+), which is released into the circulation and is called
a mature (nave) B cell when it simultaneously expresses both surface IgM+ and
IgD+ (via alternative splicing).
Each B cell can only make Ig specific to one antigen
o

Each B cell's antigen specificity (idiotype) is determined by the threedimensional shape formed by the N-terminal of heavy and light chains (at
the tips of the "Y").

B cells that are reactive to self antigens undergo clonal deletion in the bone
marrow or are inactivated in the periphery (clonal anergy).

During B-cell maturation, 4 things contribute to idiotypic diversity:

o

1) Existence of multiple allotypes of V, D, and J genes (inherited from

parents)

2) Gene recombination:
VDJ recombination diversity of heavy chain variable domains
VJ recombination diversity of light chain variable domains

3) N-nucleotide addition: Tdt (terminal deoxynucleotidyl transferase)

randomly inserts nucleotides into the DNA sequence at the junctions of V, D,
and J segments.
- In B cells, Tdt is only active during recombination of heavy chain gene
segments (VDJ recombination), not active during recombination of light
chain gene segments (VJ recombination).
- In T cells, Tdt is active during rearrangement of all gene segments in the
formation of TCR (T-cell receptor).

4) Combinatorial diversity: any heavy chain can associate with any light
chain different heavy chain-light chain combinations form different
epitopes

Once VDJ and VJ recombination are complete, allelic exclusion inactivates

one chromosome in a homologous pair ensures that only one Ig idiotype
is expressed in each B cell

T cell-dependent activation of a mature (nave) B cell (surface IgM+ and IgD+)

involves 3 steps:

1) B cell surface immunoglobulins (B cell receptors) are bound and crosslinked by their specific cognate antigen clustering of B cell receptors
triggers endocytosis of receptor-antigen complexes into the B cell cytoplasm

2) Endocytosed antigen is dissociated from the B-cell receptor and then

cross-linked to MHC class II peptides antigen-MHC II complexes are
then inserted into the B cell membrane and displayed on the B cell surface

3) TH (Helper T cells) recognize this MHC-complexed antigen and provide a

co-stimulatory signal (e.g., interaction between CD40L on the TH and CD40
on the B cell) to activate the B cell to differentiate and proliferate

There are two examples of T cell-independent activation of B cells:

o

1) Some non-protein antigens like carbohydrates [e.g., the LPS

(lipopolysaccharide) endotoxin in the cell wall of most gram-negative
bacteria] have repeating epitopes that can cross-link a large number of B cell
receptors at once clustering of B cell receptors antigen-specific T
cell-independent activation of B cells that recognize the repeated epitope

2) An antigen called a mitogen (e.g., the highly repetitive surface structure

of certain parasites) can bind B cell surface molecules that are not B cell
receptors but are nevertheless linked to B cell receptors clustering of
mitogen-bound B cell surface molecules clustering of B cell receptors
linked to the mitogen-bound B cell surface molecules polyclonal T cellindependent activation of B cells that do not recognize the inciting
mitogen. In other words, a single mitogen can activate many different B
cells with many different specificities, none of which are specific for the
mitogen!

Upon antigenic stimulation mature (nave) B cells may become either antibodyproducing plasma cells or memory B cells.
o

Somatic hypermutation (occurs in B cells only, not in T cells):

- After antigen stimulation rapid clonal proliferation of B cells (which
produce antibodies against one particular antigen) naturally occurring
mutations in this rapid process yield antibodies with varying affinities for
the antigen B cells which produce antibodies with the highest antigen
affinity are selected
- Note: this is the only change in idiotype that occurs after antigen
stimulation

Following antigen-specific activation, mature (nave) B cells are able to

produce an immunoglobulin isotype other than IgM or IgD (e.g., IgG, IgA,
or IgE) by isotype switching, which is accomplished through irreversible
genomic recombination of heavy chain constant regions.

B cell markers: CD 19, CD 20, CD 21

CD 19: co-receptor with CD21; involved in signal transduction during B cell

activation

CD 20: function unknown

CD 21 (CR2, C3d receptor): co-receptor with CD19; involved in B-cell

activation. Is also the receptor for complement component C3d

EBV (Epstein-Barr virus) gains access into B cells via CD 21 infectious

heterophil-positive mononucleosis

T cells

T cell surface markers:

o CD2 and CD3, which are important in signal transduction, are
major markers of all peripheral T cells
o

The presence of CD4 defines T helper cells; CD8 defines cytotoxic

T cells

Primary roles of T cells:

o

CD4+ Th1 cells produce interferon gamma, which activates

macrophages. CD4+ Th2 cells help B cells make antibodies.

CD8+ T cells directly kill virus infected cells

T cells are involved in delayed cell-mediated hypersensitivity (type

IV)

T cells mediate allograft rejection, both acute and chronic. [Note:

B cells are also involved in organ transplant rejection]

Helper (CD4+) T cell activation:

o

Initial step: foreign body phagocytosis by an APC (antigen

presenting cell). This is followed by two co-stimulatory signals.

First signal: The APC presents an antigen on its MHC-II. This is

recognized by the TCR (T-cell receptor) of the T helper cell

Note: the antigens presented to CD4+ T cells by MHC-II molecules

on APCs are larger than those presented to CD8 + T cells

Second signal: Interaction of B7 on the APC with CD28 on the T

helper cell production of signaling molecules (cytokines)

Cytotoxic (CD8+) T cell activation:

First signal: Antigen is presented on MHC-I of a virus-infected cell

and recognized by TCR on the T cytotoxic cell. The CD8 coreceptor reinforces this signal

Second signal: CD28 on the T cell interacts with CD80 or CD86 on

other cells (e.g. B cells) to produce a more potent T cell response.
That response involves secretion of IL-2, which stimulates T-cell
growth and differentiation

T-cell activation process.

Antibody Structure

Antibody Structure
o A "Y" shaped molecule made of 2 heavy chains and 2 light chains
o

The tips of the "Y" are the variable regions that recognize antigens

The tips involve both heavy and light chains

Heavy Chain
o

Heavy chain is part of both Fc (constant) and Fab (antigen

binding) regions

A specific amino acid sequence on the heavy chains differentiates

the Ig classes (IgG, IgA, IgM, IgE, IgD)

The C-terminal region of the Fc portion of IgG and IgM binds

complement. The Fc portion of IgA/G/E activates effector cells.

Light Chain
o

Light chain is not found in the Fc portion

All five Ig classes share a common amino acid sequence on the

light chain

Basic immunoglobulin structure.

Basic immunoglobulin structure.

Immunoglobulins

Five immunoglobulin classes: IgM, IgG, IgA, IgE, and IgD

o Igs capable of fixing complement (classic pathway): IgG, IgM
o

Igs on the surface of nave B cells: IgM, IgD

Igs on memory B cells: IgG, IgA, or IgE (but only one Ig class per
memory B cell)

IgG is the only Ig capable of :

1) Crossing the placenta

2) ADCC (antibody dependent cell-mediated cytotoxicity)

3) Opsonization

IgG (Immunoglobulin G)
o

Has four subclasses (1-4) which are differentiated by slight

variations of the heavy chain. It is the most common antibody
(composes 75% of serum Ig)

Capable of executing all the functions of the immunoglobulins

Protects the body via four mechanisms of action:

1. Agglutination and immobilization
2. Fixing/activating complement
3. Opsonization for phagocytosis
4. Neutralizing bacterial toxins

It is the only immunoglobulin which crosses the placenta

IgA (Immunoglobulin A)
o

Second most common immunoglobulin in serum, most common

immunoglobulin overall (due to vast mucosal surface area). Has a
serum half-life of 6 days

Does not fix complement

It is the primary immunoglobulin found in secretions very

important in mucosal immunity

Exists as a monomer in serum but as a dimer in secretions

When passed into secretions, it acquires a secretory piece

produced by epithelial cells. The secretory piece preserves the IgA
and assists its transport to the mucosal surface

IgM (Immunoglobulin M)
o

Third most common immunoglobulin. First Ig to be made by a B

cell that has been freshly introduced to an antigen

Pentameric structure of the secreted form of IgM makes it a good

agglutinating Ig. IgM also fixes complement.

Exists as a monomer when attached to B cell surfaces while

functioning as an antigen receptor

IgD (Immunoglobulin D)
o

Acts primarily as an antigen receptor on B cell surfaces. Also

found in small amounts in serum, but its role there is not yet clear

It does not bind complement

IgE (Immunoglobulin E)
o

It binds tightly to Fc receptors on basophils and mast cells; thus it

is the least common serum immunoglobulin

Causes release of cytokines and other mediators involved in the

allergic response when it comes in contact with an antigen. This is
type 1 hypersensitivity

Serum levels rise in parasitic infections. Helps eosinophils (which

have Fc receptors for IgE) to attack IgE-coated helminths

Systems of categorizing immunoglobulins

o

Isotype (IgG, IgA, IgM, IgD, IgE):

- determined by the primary sequence of amino acids in the
constant region of the heavy chain (which determines the 3dimensional structure of the molecule)
- antigenic determinant that divides the antibodies into different
types and subclassesisotypes are shared across an entire
species

Allotype (polymorphism):
- slight differences in the constant region of the heavy and
light chains
- unlike isotypes, which are species-wide, allotypes can vary
among members of a given species

Idiotype:
- defined by the amino acid sequence and corresponding 3dimensional structure of the variable region of the
immunoglobulin molecule
- reflects similarities in the variable region for a given antigen
among a group of Ig or T cell receptors
- idiotypes are highly variable from person to person

Immunoglobulin G

Immunoglobulin A: 1. H chain 2. L-chain 3. J-chain 4. secretory component

Immunoglobulin M: 1. base unit 2. heavy chains 3. light chains 4. J chain 5. intermolecular

disulfide bonds

The role of mast cells in the development of allergy.

Cytokines

IL-1: secreted by macrophages, B cells, monocytes, and osteoblasts

o Stimulates T helper cells, induces B cells to multiply, activates endothelial
adhesion molecules, stimulates acute inflammation, and activates osteoclasts
( bone resorption)

IL-2: secreted by T helper lymphocytes and helps to amplify the overall T cell
response

IL-3: secreted by activated T cells, mast cells, NK cells, eosinophils

o

IL-4: secreted by CD4+ Th2 cells, macrophages, and mast cells

o

Inhibits cytokine production by Th1 cells

Stimulates differentiation of B cells into plasma cells

IL-12: secreted by macrophages, Th1 cells, and B cells

Activates NK cells and promotes differentiation of naive T cells into Th1
cells

IFN-: secreted by Th1 cells, cytotoxic T cells, dendritic cells, and NK cells
o

Functions in neutrophil chemotaxis

IL-10: secreted by monocytes and to a lesser extent Th2 cells, mast cells,
macrophages

Stimulates differentiation of B cells into plasma cells, promotes antibody

secretion, and induces an acute phase reaction in T cells

IL-8: secreted by macrophages, lymphocytes, endothelial cells

o

Promotes differentiation of B cells and IgA production. Also promotes

eosinophil production.

IL-6: secreted by Th2 cells, macrophages, B cells

o

IL-4 plays a role in the allergic response by promoting B cell proliferation

and IgG/IgE synthesis; also inhibits Th1 while promoting Th2 proliferation

IL-5: secreted by Th2 cells, mast cells, and eosinophils

o

Stimulates the proliferation and differentiation of bone marrow stem cells.

Also stimulates growth of mast cells and promotes histamine release

Activates macrophages and NK cells, and suppresses Th2 cell activity

TNF-: secreted mainly by macrophages

o

Notable functions: mediates septic shock, causes leukocyte recruitment, and

causes vascular leakage

Cell Surface Proteins

Helper T cells express CD3, CD4, CD28, CD40L, and TCR (T-cell receptor)
Cytotoxic T cells express CD3, CD8, and TCR

B cells express B7, CD19, CD20, CD21, CD40, IgM, and MHC-II

Macrophages express B7, CD14, CD40, MHC-II, and receptors for Fc and C3b (a
complement component)

NK cells express receptors for MHC-I, CD16, and CD56

All nucleated cells express MHC-I (exception would be anucleate cells, such as
mature RBCs)

Complement

A system requiring nine major factors (C1-C9) which plays a role in cell
lysis, humoral immunity, and inflammation
o C3b and IgG are the two primary opsonins in bacterial defense
o

C1, C2, C3, C4 are key for viral neutralization

C3a, C4a, and C5a promote anaphylactic activity, such as

degranulation of mast cells

C5a is a potent chemoattractant: recruits neutrophils and other

inflammatory cells

C5b, C6, C7, C8, and C9 form the membrane attack complex
(MAC) which results in cell lysis

Classic Pathway: the binding of proenzyme C1 to an Ag-Ab complex

triggers a sequential reaction resulting in cell lysis
o

The immunoglobulins IgG and IgM can activate the classic

pathway of the complement system

Mannitose-binding lectin pathway: mannitose-binding lectin

replaces C1q; does not need the presence of antibodies to be
activated

Alternate Pathway: activated by cell wall components from certain

bacteria and yeasts, endotoxin, and aggregated IgA. Does not require
antibody, C1, C4, or C2

Decay accelerating factor (DAF, also known as CD55) inhibits the

assembly of C3 convertases; DAF and C1 esterase inhibitor both prevent
inappropriate complement activation [1]

Mutations of C1 esterase inhibitor can lead to hereditary

angioedema and HUS (hemolytic uremic syndrome)

Deficiency of DAF complement-mediated lysis of RBCs

paroxysmal nocturnal hemoglobinuria (PNH)

PNH (paroxysmal nocturnal hemoglobinuria):

PNH is caused by acquired, inactivating somatic mutations in

the PIGA (phosphatidylinositol glycan complementation
group A) gene in hematopoietic stem cells deficiency of GPI
(glycosylphosphatidylinositol)-linked proteins, including 3
GPI-linked proteins that regulate complement (decay-accelerating
factor (CD55), membrane inhibitor of reactive lysis (CD 59), C8
binding protein) susceptibility of RBCs, WBCs, and
platelets to complement-mediated lysis

The hemolysis in PNH is usually chronic (as opposed to

paroxysmal) and occurs throughout the day (as opposed to
nocturnal), and the hemoglobinuria of PNH is usually not dramatic
the hemolysis is only paroxysmal and nocturnal in 25% of cases
( respiratory rate during sleep respiratory acidosis blood
pH complement activity, hence the increased tendency for
RBCs to lyse at night in ~25% of patients with PNH)

Suspect PNH in patients with:

1. Hemolytic anemia (intravascular hemolysis secondary to
C5b-C9 membrane attack complex formation)
2. Hypercoagulable state due to platelet dysfunction
(secondary to deficient GPI-linked proteins on platelets)
recurrent venous thrombosis is common, often involving the
portal vein, hepatic veins, or cerebral veins; thrombosis =
most common cause of death in PNH
3. PancytopeniaPNH is often associated with aplastic
anemia (ie, bone marrow failure)

PNH is now diagnosed by demonstrating RBCs deficient in GPIlinked proteins (eg, decay-accelerating factor (CD55), membrane
inhibitor of reactive lysis (CD 59), C8 binding protein) on flow
cytometry.
Classic tests for PNH:
- Screen for PNH with sucrose hemolysis (sugar water) test
- Confirm PNH with acidified serum (Ham) test: acidified serum
activates alternative complement pathway to cause hemolysis

Lack of C3 or any other activator proteins can predispose to severe,

recurrent pyogenic sinus and respiratory tract infections

Deficiency of the terminal pathway (C6, C7, and C8) predisposes to

Neisseria infections

The complement pathway

Interferons

Interferons are cytokines that are produced in response to the presence of viruses,
parasites, and tumor cells
They have antiviral properties: IFN- is one treatment for chronic hepatitis C
infection [1]

IFNs activate macrophages, thereby the presentation of antigens to T cells.

IFNs also activate and enhance the functionality of NK cells.

Interferons can pass through the blood-brain barrier

IFN- delayed-type hypersensitivity; this involves activation of macrophages and

the release of TNF-

Passive & Active Immunity

Passive Immunity
o The transfer of active humoral immunity (e.g. antibodies) from one
individual to another (e.g. IVIG infusions)
o

Not produced by the patients body, immunity persists only as long as the
antibodies are in the body

Other examples of passive immunity: human tetanus immune globulin given

to treat tetanus, a baby receiving antibodies in his mothers breast milk

Active Immunity
o

Acquired after exposure to a foreign agent such as an infection or a

vaccination, usually involves both cell-mediated and humoral immunity

Memory B and T cells develop after initial exposure to foreign antigens

reinfection rapidly activates these memory cells

Usually lasts for the lifetime of the patient, but vaccine-induced immunity
can wane over time (see "Loss of Vaccine-Induced Immunity to Varicella
over Time")

Antigen Diversity
o

Process by which an infectious organism changes its surface proteins in

order to evade a host immune response

Occurs through gene mutation, recombination, and switching. It leads to

more resilient organisms

Bacteria can alter some molecular structures (e.g. Salmonella acquiring

antigenically distinct flagellar proteins)

Antigenic drift is the process of random accumulation of mutations in viral

genes; can be recognized by the immune system

Antigenic shift is the process by which at least two different strains of a

virus (or different viruses), combine to form a new subtype having a mixture

of the surface antigens of the two original strains. This is how viruses can
migrate from one species to another (i.e. pigs to humans)
o

Influenza shift includes rearrangement of its viral genomic RNA segments;

shifts represent drastic changes and can cause pandemics. Drift includes
more minor changes due to mutation of hemagglutinin and/or
neuraminidase.

Anergy
o

Lack of reaction by the bodys immune system to antigens

T-cell anergy can arise when the T-cell receives only 1 of the 2 required
stimulatory signals during antigen recognition

Clinical example: in lepromatous leprosy, the cellular response to many nontuberculoid antigens is suppressed

B-cell anergy is a key mechanism for self-tolerance in B-cells

B-cell anergy can occur with exposure to a circulating autoantigen, and is

marked by surface IgM levels and modification of intracellular signaling
pathways

B-cell anergy is less complete than in T cells

Type I Hypersensitivity

Type I Hypersensitivity: immediate or anaphylactic

Mast cell-bound or basophil-bound IgE crosslinks an allergen triggers
degranulation, releasing histamine, tryptase, kinogenase,
prostaglandins, platelet aggregating factor, and other allergic agents.
Since no products need to be synthesized by the cell, this process is
rapid.
o

Chemotactic factors (for eosinophils and neutrophils) are also

released, which ultimately triggers release of additional factors
from those cells

Increased serum IgE levels during a reaction may indicate an atopic

reaction (atopy is a systemic reaction)
o

1) Allergic rhinitis (hay fever): most common form of atopy

2) Urticaria: cutaneous form with vasodilation and increased

vascular permeability of the skin

3) Asthma: obstruction due to mucus secretion and smooth

muscle contraction surrounding bronchioles

Allergic rhinitis (hay fever) is the most common clinical expression of

atopy
o

Caused by binding of allergen to IgE which releases histamine,

leukotrienes, prostaglandin D2, and eosinophil chemotactic factor
(ECF)

Definitive treatment involves repeated subliminal doses to

allergens. This enables the synthesis of circulating IgG, which
combines avidly with the repeat exposure of circulating allergens
and prevents activation of IgE-antigen induced inflammatory
mediators.

Anaphylaxis: a severe, systemic reaction that occurs when the allergeninduced mediators are released systemically
o

The major mediators of anaphylaxis are TNF-, IL-1, IL-6, platelet

activating factor (PAF), leukotrienes, prostaglandins, and
histamine

Anaphylaxis

Type II Hypersensitivity

Type 2 HSRs (type II (antibody-mediated) hypersensitivity reactions): IgM

and/or IgG autoantibodies bind fixed antigens in specific tissuesie, there are no
circulating immune complexes type 2 HSRs are usually tissue-specific instead of
systemic (vs. type 3 HSRs which involve circulating immune complexes and are
usually systemic)
o 2 categories of pathogenesis in type 2 HSRs:
o

1) Cytotoxic: antibodies can bind and initiate cytotoxicity via a variety of

mechanisms, including:
- Opsonization and phagocytosis
- Complement-mediated inflammation and tissue damage
- Fc receptor-mediated inflammation and tissue damage (also known as
ADCC (antibody-dependent cell-mediated cytotoxicity))

2) Non-cytotoxic: antibodies can bind and interfere with normal function

for example:
- Myasthenia gravis: anti-ACh (acetylcholine) receptor antibodies bind
postsynaptic ACh receptors prevents ACh from binding postsynaptic ACh
receptors + induces downregulation of postsynaptic ACh receptors
- Graves disease: anti-TSH receptor antibodies bind and thereby stimulate
TSH receptors
- Pernicious anemia: anti-IF (intrinsic factor) antibodies bind and thereby
prevent IF from binding with vitamin B12 absorption of vitamin B12 in
the ileum

Examples of Type II (antibody-mediated) hypersensitivity include:

o

1) ITP (idiopathic (immune) thrombocytopenic purpura, also known as

autoimmune thrombocytopenic purpura): antibodies against platelet
membrane proteins (eg, GpIIb:IIIa integrin) opsonize platelets and/or
activate complement complement-mediated platelet lysis and/or
phagocytosis by neutrophils and macrophages bleeding due to
quantitative platelet deficiency

2) Autoimmune hemolytic anemiafor example:

- Erythroblastosis fetalis (also known as hemolytic disease of the newborn)
- Transfusion reactions (eg, blood group (ABO, Rh, Kidd, Kell)
incompatibility): preformed antibodies in the recipient's blood opsonize
donor RBCs and/or activate complement complement-mediated RBC
lysis and/or rapid phagocytosis by neutrophils and macrophages
hemolysis, anemia

3) Pemphigus vulgaris: anti-desmosome antibodies (eg, IgG1 and/or IgG4

antibodies against desmoglein-1 and/or desmoglein-3) flaccid, easily
ruptured intraepidermal bullae + positive Nikolsky sign (gentle rubbing of
unaffected skin separation of epidermis)

4) Acute rheumatic fever: antibodies against streptococcal wall antigen

cross-react with joint and myocardial antigens arthritis, myocarditis

5) Graves disease: anti-TSH receptor antibodies bind and thereby stimulate

TSH receptors hyperthyroidism

6) Goodpasture syndrome: anti-GBM (glomerular basement membrane)

antibodies react with the Goodpasture antigen (a peptide within the
noncollagenous domain of the 3 chain of type IV collagen) in GBMs and
also cross-react with pulmonary alveolar basement membranes
complement activation releases C5a (potent chemotactic factor)
recruitment of neutrophils, which mediate tissue damage by the lysosomal
enzymes within their azurophilic granules nephritis (hematuria) +
pulmonary hemorrhage (hemoptysis)

7) Myasthenia gravis: anti-ACh (acetylcholine) receptor antibodies prevent

ACh from binding postsynaptic ACh receptors and also induce the
downregulation of postsynaptic ACh receptors paresis (muscle
weakness), paralysis

8) Vasculitis caused by ANCA

9) Pernicious anemia: anti-IF (intrinsic factor) antibodies bind and thereby

prevent IF (produced by parietal cells lining the stomach) from binding with
vitamin B12 absorption of vitamin B12 in the ileum B12 deficiency
Megaloblastic macrocytic anemia: B12 deficiency cannot get methyl
group off of folate dTMP synthesis defect in DNA synthesis
cannot make as many cells as normal (hence anemia) + cannot
mature/condense nuclei or cells (hence megaloblastic macrocytic)
Neurologic deficits: B12 deficiency defect in propionate (odd-chained
fatty acid) metabolism defect in synthesis of CNS myelin subacute
combined degeneration due to demyelination of:
- Dorsal columns (cuneate and gracile nuclei and tracts) impaired
position/vibration sense (positive Romberg test)
- Lateral corticospinal tracts signs of upper motor lesion (hyperreflexia,
muscle tone, positive Babinski with toes upgoing/extending and fanning out
upon stimulation of plantar aspect of foot)
- Spinocerebellar tracts ataxic gait

Hemolytic disease of the newborn (erythroblastosis fetalis): transplacental transfer

of maternal anti-Rh IgG (usually anti-RhD) binds to Rh+ fetal RBCs fetal RBCs
are destroyed (relative hypoxia, altered cellular metabolism)
o

Prevention of erythroblastosis fetalis is required when the mother is Rh- and

her fetus is Rh+: administer anti-Rh antibody (RhoGAM) to the mother at 28
weeks gestation and again within 1-2 days of delivery to neutralize fetal Rh

antigens that enter the mothers circulation during placental delivery this
prevents stimulation of the maternal immune system and injury to future Rh+
newborns

Type III Hypersensitivity

Type III Hypersensitivity: immune complex reactions

Circulating antigen-antibody complexes deposit on the surface of blood
vessels activating complement. Neutrophils are attracted release
lysosomal enzymes tissue destruction
o

1) Arthus Reaction: rare, severe inflammatory response to gross

intravascular antigen-antibody complex precipitates of intermediate size
o

Examples include: SLE (systemic lupus erythematosus), RA

(rheumatoid arthritis), PAN (polyarteritis nodosum), PSGN
(poststreptococcal glomerulonephritis), serum sickness, Arthus
reaction, and hypersensitivity pneumonitis

Occurs in highly sensitized humans injected with antigen

complement is activated chemotactic factors (C3a, C5a) cause
neutrophil infiltration and platelets produce thrombi, ultimately
yielding hemorrhagic, necrotic lesions

2) Serum sickness: formed immune complexes deposit in membranes

where they fix complement tissue damage
o

Caused by injection of foreign serum or drugs (e.g. sulfonamides,

penicillin, cephalosporins, phenytoin, and thiourea)

Patients present with fever, pruritic rash, proteinuria,

lymphadenopathy, and joint pain

Following the first exposure to an antigen, it takes 7-14 days for

IgM antibodies to be produced in serum sickness (production of
IgG follows IgM).
If a previously immunized patient is later re-exposed to the same
antigen, memory B cells formed by the previous antigenic
exposure can produce an IgG response within 12-36 hours,
producing a much more acute and severe serum sickness
reaction.
[1] [2] [3]

3) Polyarteritis nodosa: continuous inflammation of arterial walls

(medium and small arteries only) secondary to the deposition of
circulating immune complexes thrombosis and obliteration of the

arterial lumen (no blood flow) distal gangrene / focal necrosis of end
organs (e.g. kidneys, but doesnt affect lungs)
o 30% of patients have hepatitis B surface antigen-antibody
complexes; loose association with p-ANCA
[4]

4) Glomerulonephritis: antigen-antibody complexes deposit on the renal

glomerular basement membrane inflammatory response
o Most commonly implicated antigens: DNA, insulin, thyroglobulin,
group A streptococci, and foreign serum
o

Diagnosis: complexes detected using fluorescent antibody against

the antigen, antibody, or complement. A "lumpy-bumpy" pattern
of fluorescence results from the random deposition of the
complexes.

5) SLE: formation of autoantibodies to endogenous antigens such as

double stranded RNA (dsRNA), nuclear antigens (ANA-antinuclear
antibodies, anti-dsDNA), as well as RBCs, WBCs, and platelets,

6) Rheumatoid Arthritis: complexing of antigen and antibody alters the

tertiary structure of the antibody the structural alteration reveals
previously buried amino acid sequences "foreign" to the immune system.
o

These newly available epitopes stimulate the production of an

antibody called rheumatoid factor (usually IgM)

Rheumatoid factor can react with the Fc domain of IgG molecules

(antibody against an antibody) resulting in IgM-IgG complexes that
deposit in synovial tissue, where they activate complement and
chemokines

Neutrophils attempt to phagocytize the complexes and release

lysosomal enzymes, destroying articular cartilage (hence arthritis)

Clinical features of systemic lupus erythematous

Rheumatoid arthritis

Type IV Hypersensitivity

Type IV Hypersensitivity: cell-mediated or delayed type response

o Cytotoxic T cells, monocytes, and macrophages cause direct
tissue damage

Involved in the pathogenesis of many infectious and autoimmune

disease processes. 3 main types: granulomatous, tuberculin type, and
contact response
o

Examples include: Type I Diabetes Mellitus, multiple sclerosis,

Guillan-Barre syndrome, Hashimotos thyroiditis, graft-versus-host

disease, PPD for Mycobacterium tuberculosis, contact dermatitis,

and granulomatous reactions

1) Tuberculin test (PPD): injection of antigen Langerhans cells present

the antigen to previously sensitized T cells yields an indurated,
erythematous lesion
o

Histologically, the inflammatory response occurs around the small

vessels (perivascular cuffing)

2) Granulomatous reactions: occur if antigen persists in the tissues and

continues to stimulate host reactivity. IFN- promotes macrophage
retention and monocyte fusion epithelioid cell granuloma

3) Contact dermatitis: haptens (small-molecular-weight chemicals) or

irritants are deposited into the skin
o

Common agents causing contact dermatitis: nickel,

dinitrochlorobenzene, rubber, poison ivy, and poison sumac

The hapten becomes antigenic when it combines with intradermal

proteins as carriers via NH3 or S-groupings

Positive tuberculin test

Contact Dermatitis

Bruton's Agammaglobulinemia

X-linked recessive disorder (male infants) caused by a mutation in the Bruton's

Tyrosine Kinase (BTK) gene, which is necessary for maturation of B cells into
plasma cells.
o Plasma cell deficiency low or no levels of all classes of immunoglobulins

Usually diagnosed when levels of maternal IgG decline (around 4-6 months of age)
and the child repeatedly develops bacterial infections.
o

Cell-mediated immunity is unaffected the immune response against viral

infections remains robust

All organs that normally contain mature B cells (lymph nodes, tonsils and spleen)
may be smaller. Germinal centers are histologically absent in these organs.

Heterozygous female carriers of the BTK mutation have no symptoms.

DiGeorge's Syndrome (Thymic Hypoplasia)

Failure of development of the 3rd and 4th pharyngeal pouches hypoplasia of the
thymus and parathyroid glands congenital T cell deficiency
o Genetics: chromosome 22q11.2 deletion syndrome (ie, there is a deletion of
about 30-40 genes at location 11.2 on the long arm of chromosome 22)

Secondary cases result from teratogen (e.g. alcohol) exposure during weeks 4-6 of
fetal development

Clinical manifestations
o

Recurrent viral and fungal infections from T cell deficiency

Tetany from hypoparathyroidism with hypocalcemia

Associated with congenital defects of heart and great vessels, mandible, and ear
aka velocardiofacial syndrome (VCFS)

Congenital heart disease is the most common cause of death. Severe immune
deficiency is the second most common cause

DiGeorge syndrome with tetralogy of Fallot(TOF) and absent pulmonary valves.

Severe Combined Immunodeficiency Disease

Caused by any one of a variety of defects in early stem cell differentiation

marked deficiency of both B and T cells both humoral and cell-mediated
immune responses are affected.
Patients present with recurrent opportunistic infections (bacterial, viral, fungal,
protozoan), chronic diarrhea, and lesions of the throat and mouth.

High incidence of malignant lymphomas

Occurs in both autosomal recessive and X-linked recessive forms

X-linked recessive form accounts for 50-60% of cases more common in boys

Mutation: -chain of cytokine receptors defective signaling of IL-2, IL-4,

IL-7, IL-15, and others

IL-7 is necessary for lymphoid progenitor (esp. T cell) survival and

proliferation

Absent helper T cells diminished antibody production

IL-15 deficiency: numbers of NK cells

Autosomal recessive deficiencies also cause SCID:

o

50% of autosomal recessive cases are caused by ADA (adenosine

deaminase) deficiency:
Lack of ADA accumulation of dATP high levels of dATP inhibit
ribonucleotide reductase (enzyme responsible for generating dNTPs from
rNTPs) absence of dNTPs prevents cells from undergoing rapid DNA
replication (e.g., lymphocytes in response to antigenic stimulation).

Bare Lymphocyte Syndrome is another autosomal recessive form of SCID

that is caused by mutations in the genes required to express MHC-II.

Omenn Syndrome is an autosomal recessive form of SCID that is caused by

nonsense mutations in the genes involved in early VDJ recombination
(RAG1 or RAG2) without VDJ recombination these patients cannot
produce functional lymphocytes.

Less commonly, a mutation in JAK3 (chr. 19), which is the target of the IL-2
receptor (afflicted in the X-linked form), can result in SCID.

Interleukin 12 Receptor Deficiency

Discovered in otherwise healthy patients with disseminated mycobacterial and

salmonella infections
The IL-12 receptor deficiency decreased production of IFN- by Th1 cells and
NK cells
IFN- is still secreted in an IL-12 independent manner so granulomas form, but the
infection is inadequately controlled by the cell-mediated immunity

Hyper IgM Syndrome

Characterized by the failure of antibodies to switch classes from IgM to

IgA/IgG/IgE once an antigen is recognized
Caused by defective CD40 ligand (CD154): CD4+ T helper cells, which normally
express CD40L, are unable to induce B cells to undergo immunoglobulin class
switch (from IgM to other classes)
Presents in infancy with recurrent upper and lower respiratory infections, often with
opportunistic organisms (e.g. Pneumocystis jiroveci)
o

Diagnosis: very low levels of IgG/IgA/IgE, patients typically have a low

number of neutrophils, IgM levels can be elevated or normal

The most common form is inherited as an X-linked trait only present in boys
o

Other, much rarer, forms of Hyper IgM syndrome exist that affect both
genders and are autosomal recessive.

Wiskott-Aldrich Syndrome

Humoral immunodeficiency caused by an X-linked recessive defect in the WASP

gene (chromosome 11) and characterized by activation of B cells and poor
antibody response to polysaccharide antigens. [1]
o WASP is involved in:
- Actin polymerization

- Anchoring membrane bound receptors (eg, antigen receptors) to the actin

cytoskeleton.

This defect in the WASP gene results in an inability to mount an IgM

response to polysaccharide antigens decreased IgM levels.

In classic WAS:
- IgM levels
- IgA and IgE levels
- IgG levels are normal.

Classic triad"TIE":
1) Thrombocytopeniamay result in purpura, bleeding
2) recurrent pyogenic Infectionseg, otitis media, pneumonia
3) chronic Eczema
In addition, defects in WASP also result in:
- Small ineffective platelets
- risk of autoimmune disease

12% chance of developing Non-Hodgkins Lymphoma

Job Syndrome (Hyper IgE Syndrome)

Characterized by neutrophil chemotaxis, which leads to recurrent staphylococcal

infections that are cold to the touch.
Caused by failure of T helper cells to produce IFN-, which is required for
macrophage activation and migration.

Presents with recurrent staphylococcal infections, eczema-like skin rashes, severe

lung infections resulting in pneumatoceles, and elevated concentrations of serum
IgE antibody

The autosomal dominant form of the disease presents with recurrent fractures,
scoliosis, coarse facies, and failure to lose primary teeth

Pneumatocele: CT image shows bilateral thick-walled lung cysts, predominantly in the

right upper lobe.

Leukocyte Adhesion Deficiency Syndrome

A rare primary immunodeficiency characterized by defective phagocytic cells and

marked leukocytosis due to defective/absent integrin proteins on phagocytic
cells
o A WBC differential will reveal extremely elevated levels of neutrophils (610x normal) because the integrin defects leave them unable to leave the
blood vessels

Defective integrin proteins (eg, LFA-1, Mac-1) on phagocytes

1) Defective phagocytosis
2) Defect in binding to endothelial cells defective transmigration out of the
bloodstream to sites of infection and/or inflammation
o

Most patients express no CD18, an essential 2-integrin on lymphocytes,

macrophages, and neutrophils which is required for:
1) Lymphocyte interactions with antigen presenting cells (e.g., neutrophils,
dendritic cells)
2) Leukocyte adhesion to endothelial cells, which is a necessary first step for
leukocyte migration to sites of infection and inflammation
3) Phagocytosis of bacteria opsonized with complement component C3b
(specifically iC3b, a proteolytically inactive form of C3b capable of
opsonization).

Leukocyte adhesion deficiency presents in the neonatal period as recurrent

bacterial infections, including:
o

Omphalitis

Pneumonia

Gingivitis

Abscesses

Peritonitis

Omphalitis: infection of the umbilical cord stump in the neonatal newborn period.

Chediak-Higashi Syndrome

Autosomal recessive disorder use the mnemonic "BALIN":

o Bleeding and bruising due to platelet dysfunction.
o

partial Albinism due to defective melanocytes

Leukopenia (especially neutropenia) recurrent pyogenic staph and strep

Infections.
[1]

peripheral Neuropathy.
Pathophysiology is due to 2 defects:
o

Defect in the synthesis, maintenance and storage of secretory granules (e.g.,

lysosomes in leukocytes, azurophilic granules in neutrophils, dense bodies in
platelets, melanin granules in melanocytes) defective granules which
tend to fuse and form giant (mega) granules. Platelets and neutrophils
with giant granules visible on peripheral blood smear are highly suggestive
of Chediak-Higashi given the appropriate clinical context.

Defect in the LYST (lysosomal trafficking) protein defect in

microtubule function in neutrophils and macrophages
1) defective chemotaxis
2) prevents fusion of lysosomes w/ phagosomes formation of
phagolysosomes bactericidal defect

Chronic Granulomatous Disease

XLR (X-linked recessive) or AR (autosomal recessive) deficiency in NADPH

oxidase ROS (e.g., superoxide) formation within phagocytes respiratory
burst and failure to kill phagocytosed catalase-positive pathogens.
o Chemotaxis and phagocytosis are intact.

S/Sx observed in patients with CGD (chronic granulomatous disease):

o

1) Recurrent infections (e.g., osteomyelitis; deep soft tissue abscesses;

severe pneumonia) w/ catalase-positive organisms
- lymphadenopathy
- hypergammaglobulinemia
- white blood cell count

2) Inadequate neutrophil defense macrophages wall off microbes and

form granulomas hepatosplenomegaly secondary to granuloma
formation

Dx: negative NBT (nitroblue tetrazolium) dye reduction test; phagocyte oxidase
negative
o

Normal phagocytes exposed to NBT develop blue inclusions indicative of a

normal respiratory burst. If blue inclusions don't develop, the test is negative
and suggests CGD.

Catalase-positive organisms are phagocytosed but cannot be killed because they

degrade their own H2O2
o

Because enzyme-deficient neutrophils cannot produce H2O2 and bacterial

H2O2 is destroyed by bacterial catalase, H2O2 is not available as a substrate
for myeloperoxidase the myeloperoxidase-halide bacteriocidal system
fails to kill catalase-positive organisms.

Remember catalase-positive organisms "SPANS KEC":

S. aureus
Pseudomonas
Aspergillus
Nocardia
Serratia
Klebsiella
E. coli
Candida

Catalase-negative organisms are phagocytosed and killed because they produce and
excrete sufficient H2O2 to permit oxygen-dependent myeloperoxidase-halide
bactericidal activity
o

NADPH oxidase-deficient neutrophils cannot produce their own ROS (e.g.,

superoxide) and thus cannot produce H2O2 either.
However, bacterial H2O2 is produced and excreted by catalase-negative
organisms in sufficient amounts NADPH oxidase-deficient phagocytes
can hijack this exogenously produced H2O2 and use it as substrate for their
myeloperoxidase-halide bactericidal system kill catalase-negative
organisms!

Chronic Mucocutaneous Candidiasis

Chronic C. albicans infections caused by a limited defect of helper T cell function

Pathophysiology: T cell cytokine production, specifically IL-2 and IFN-
o

Can also occur in patients lacking T cell immunity (e.g. DiGeorge

syndrome)

Presents in infancy with cutaneous, mucous membrane, or disseminated candidal

infections

Associated with several genetic disorders, including autoimmune

polyendocrinopathy syndrome type I (APCED), thyroid disease (chromosome 2p),
and hyper-IgE syndrome

Image of a SABHI agar plate culture of the fungus Candida albicans grown at 20C.

Oral Thrush

Isolated IgA Deficiency

Most common inherited B cell defect, occurs in 1 in 700 persons

Represents a failure of terminal differentiation of IgA-producing B cells: they never
mature to plasma cells IgA levels are nearly undetectable
o

Because the defect is specific to IgA-lineage B cells, the other

immunoglobulins are normal

Presents with upper respiratory tract infections, anaphylactic reactions to transfused

blood, infections (especially those involving mucosal surfaces), diarrhea, and milk
allergies

Show help

Ataxia-Telangiectasia

Ataxia-Telangiectasia is an autosomal recessive disease caused by defective ATM

protein. The ATM gene (chromosome 11) is normally involved in repair of doublestrand DNA breaks defective ATM defective repair of double-strand DNA
breaks

1. Cells become sensitive to X-ray irradiation (because X-rays have

sufficient energy to cause double-strand DNA breaks), but not to UV
irradiation (which causes formation of aberrant thymine-thymine dimers and
other more subtle forms of DNA damage)

2. Defective antibody class switching (ie, the switch from IgM to other
antibody classes is defectivegene splicing and rearrangement are required
to switch antibody class this process becomes defective when doublestrand DNA breaks cannot be remedied) levels of IgG, IgA, IgE
patients have a median lifespan of 20 years due to severe, recurrent
sinopulmonary infections

In addition to radiation sensitivity and recurrent sinopulmonary infections, AtaxiaTelangiectasia is also characterized by:
Development of ocular telangiectasias, usually by age 5

1.

Compromised cerebellar development, with onset of truncal ataxia as a toddler and

later development of peripheral ataxia with chorea, athetosis, dystonia, and myoclonus
2.

Telangiectasia.

Autoantibodies and Associated Disorders

Anti-nuclear antibodies (ANA) and systemic lupus erythematous (SLE)

o Anti-dsDNA and anti-Smith are specific for SLE
o

Anti-histone is associated with drug-induced lupus

Anti-IgG (Rheumatoid factor) and rheumatoid arthritis

Anti-centromere and scleroderma (CREST)

o

Anti-Scl-70 and scleroderma (diffuse type)

Anti-mitochondrial and primary biliary cirrhosis

Anti-gliadin and celiac disease

Anti-basement membrane and Goodpastures syndrome

Anti-epithelial cell and anti-desmoglein are associated with pemphigus

vulgaris

Anti-microsomal and antithyroglobulin are associated with Hashimotos

thyroiditis

Anti-Jo-1 and polymyositis or dermatomyositis

Anti-SS-A (anti-Ro) and Anti-SS-B (anti-La) associated with Sjogrens

syndrome

Anti-U1 RNP (ribonucleoprotein) and mixed connective tissue disease

Anti-smooth muscle and autoimmune hepatitis

Anti-glutamate decarboxylase and Type I diabetes mellitus

c-ANCA and Wegeners granulomatosis

p-ANCA and Churg-Strauss syndrome, microscopic polyangiitis and focal

necrotizing and crescentic glomerulonephritis

Clinical features of lupus on a childs face.

Most patients (over 80%) have vascular symptoms and Raynauds phenomenon, which
leads to attacks of discoloration of the hands and feet in response to cold.

Rheumatoid arthritis: joint space narrowing and carpal crowding with collapse of the
proximal rows. Osteophytosis is seen at the distal radioulnar joint.

CREST

Primary biliary cirrhosis is a chronic disease that causes the bile ducts in the liver to
become inflamed and damaged and, ultimately, disappear.

This picture shows a chronic inflammatory disease (dermatitis herpetiformis) that produces
red (erythematous), raised (papular), small or large blisters (vesicles or bullae) that burn
and itch intensely. Dermatitis herpetiformis develops suddenly, lasts for weeks to months,
and may be associated with digestive diseases (such as Celiac disease).

Pemphigus vulgaris is an autoimmine disorder, where the bodys immune system attacks
some of the proteins in the skin. Pemphigus usually occurs in middle-aged or older people.
This picture shows a close-up of the blistering on the back. Most of the blisters have broken
(denuded), which is common since these blisters are fragile.

Chronic thyroiditis (Hashimotos disease) is a slowly developing persistent inflammation of

the thyroid which frequently leads to hypothyroidism, a decreased function of the thyroid
gland. Middle-aged women are most commonly affected.

The parotid gland is at the edge of the jaw and can become swollen and inflamed in some
people with Sjgrens Syndrome.

Immunofluorescence pattern produced by binding of ANCA from a patient with Wegeners

Granulomatosis to ethanol-fixed neutrophils

HLA-Subtypes

Listed below are HLA-subtypes with their associated pathological conditions

HLA-A3: hemochromatosis

HLA-B27: psoriasis, ankylosing spondylitis, inflammatory bowel disease, Reiters

syndrome

HLA-B8: Graves disease, celiac sprue

HLA-DQ2, HLA-DQ8: celiac disease

HLA-DR2: multiple sclerosis, hay fever, systemic lupus erythematous,

Goodpastures

HLA-DR3: DM1 (in addition to HLA-DR4)

HLA-DR4: rheumatoid arthritis, Type I diabetes mellitus

HLA-DR5: pernicious anemia due to vitamin B12 deficiency and Hashimotos

thyroiditis

HLA-DR7: steroid-responsive nephrotic syndrome (minimal-change disease) [1]

Grafts

Grafts: tissue transferred from one location to another to provide structure and/or
function
Allo- and xenografts require immune suppression

1) Autograft: self grafts.

Bone marrow, skin grafts, cartilage, and bone

2) Syngeneic graft: from an identical twin or clone

3) Allograft: from another individual of the same species

o

Examples include skin transplants, corneal transplants, heart transplants,

liver transplants, and bone marrow transplants

4) Xenograft: grafts from a different species

o

Example: bovine (cow) heart valves

These types of grafts have the highest incidence of immune rejection

Cyclosporine

Preferentially binds to cyclophilin to form a complex which inhibits calcineurin

o Calcineurin inhibition leads to a decrease in the synthesis of IL-2 and its
receptor by CD4+ Th cells, therefore decreasing T-lymphocyte proliferation.
o

Remember: auto-stimulation by IL-2 is the main stimulus for T cell

proliferation.

Preferentially suppresses cell mediated reactions whereas humoral immunity is

affected to a far less extent

Used to prevent rejection of kidney, liver, and cardiac allogenic transplants

Cyclosporine is more effective when used in conjunction with

glucocorticoids

Can also be used to treat rheumatoid arthritis and recalcitrant psoriasis

Most common adverse effect: nephrotoxicity [1]

Cyclosporinethe most common cause of a rise in BUN and creatinine

levels post-transplantation
Note: Cyclosporine toxicity responds promptly to reductions in dosage.
Best preventive strategy: Restrict cyclosporine doses to the lowest effective
level
Best guide to dosage: careful assessment of adverse effects
Measuring cyclosporine levels: via TDx monoclonal assay

Other adverse effects:

- gingival hyperplasia
- hirsutism
- risk of viral infections (HSV, CMV)
- lymphomas
- anaphylaxis
- hyperkalemia
- hypertension
- tremor
- glucose intolerance

Metabolites are mainly excreted via the biliary system

o

Only a small amount of the parent drug appears in the urine

Tacrolimus (FK506)

10 to 100 times more potent than cyclosporine

Binds FK binding protein, inhibiting secretion of IL-2
o

IL-2 is the main stimulus for T-lymphocyte proliferation

Compare this mechanism of action to that of cyclosporine

Used to prevent rejection of liver and kidney transplants

Preferred to cyclosporine: fewer rejection episodes and lower glucocorticoid

requirement
o

Remember, glucocorticoids also immune function and can therefore the

rate of infections

Most of the drug and its metabolites are excreted in the feces

Toxicities include: nephrotoxicity, neurotoxicity (tremor, seizures, hallucinations),

hypertension, pleural effusion, and hyperglycemia
o

Unlike cyclosporine, tacrolimus does not cause hirsutism or gingival

hyperplasia

Azathioprine

Contains a nitroimidazoloyl side chain attached to the sulfur of 6-mercaptopurine,

which is removed by non-enzymatic reduction by glutathione to yield 6mercaptopurine
o 6-mercaptopurine is then converted to the corresponding nucleotide,
thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthineguanine phosphoribosyl transferase
o

The immunosuppressant effects are due to TIMP, which functions as a

fraudulent nucleotide

Azathioprine is toxic to proliferating T lymphocytes

Clinical uses:
o

Kidney transplantation

Autoimmune disorders (e.g. glomerulonephritis, rheumatoid arthritis,

hemolytic anemia)

Toxicities include bone marrow suppression

Toxic effects may be increased by allopurinol. Remember, the active metabolite

mercaptopurine is metabolized by xanthine oxidase.

Muromonab-CD3 (OKT3)

A murine monoclonal antibody that binds to the -chain of CD3 on the surface of T
cells
o Muromonab-CD3 modulates the CD3/T cell receptor complex and blocks
cellular interaction with CD3, which is involved in signal transduction.

Uses: treatment of acute rejection of renal allografts

Treatment of steroid resistant acute allograft rejection in cardiac and hepatic

transplant patients

Also used to deplete T cells from donor bone marrow prior to transplantation

Toxic effects include cytokine release syndrome. Manifestations of this syndrome

range from a mild, flu-like illness to a life-threatening shock secondary to severe
peripheral vasodilation.
o

Anaphylactoid reactions can occur. CNS effects include seizures,

encephalopathy, cerebral edema, aseptic meningitis, and headaches.

Contraindicated in patients with history of seizures, uncompensated heart failure,

pregnant women, and those breast feeding

Sirolimus (Rapamycin)

Mechanism: complexes with FK-binding protein 12 the sirolimus-FKBP12

complex binds to mTOR (mammalian target of rapamycin) inhibits the action of
IL-2 on T and B cells
o Compare: sirolimus prevents IL-2 from activating T and B cells, whereas
tacrolimus prevents IL-2 secretion

Used in immunosuppression after kidney transplants because it has no

nephrotoxicity
o

Used in combination with cyclosporine and corticosteroids.

Toxic effects include: hyperlipidemia, thrombocytopenia, and leukopenia

Mycophenolate mofetil

Reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase,

blocking the de novo formation of guanosine phosphate (GMP)
o Similar to azathioprine/6-MP, this mechanism action deprives rapidly
proliferating T and B cells of nucleic acids

Adverse effects include pain, diarrhea, leukopenia, sepsis, and lymphoma

Absorption of this drug is decreased if co-administered with antacids containing

magnesium, aluminum or cholestyramine

Daclizumab

A monoclonal antibody to the -subunit of IL-2 receptor of T cells

Used as an immunosuppressant for kidney transplants as it prevents incidence and
severity of acute rejection in kidney transplantation without increasing the incidence
of opportunistic infections

Recombinant Cytokines

IL-2 (aldesleukin) is used to treat renal cell carcinoma and metastatic melanoma
Erythropoietin (EPO) is produced by the peritubular capillary endothelial cells in
the kidney. It controls erythropoiesis and is used to treat anemia, especially when
the kidney can no longer produce it

Granulocyte colony-stimulating factor (GCSF) is used to stimulate bone marrow to

produce stem cells, neutrophils, and granulocytes

Granulocyte-macrophage colony-stimulating factor (GM-CSF; e.g., sargramostim)

is used to stimulate stem cells to produce granulocytes, which are precursors for
neutrophils, basophils, and eosinophils

Interferon- is used to treat hepatitis B and C, Kaposis sarcoma, leukemias, and

malignant melanoma

Interferon- is used to treat multiple sclerosis by acting as an anti-inflammatory and

maintaining the integrity of the blood-brain barrier

Interferon- is used to treat chronic granulomatous disease and hepatitis C

IL-11 (oprelvekin) is a thrombopoietic growth factor that directly stimulates the

proliferation of hematopoietic stem cells and megakaryocyte progenitor cells. Result
is increased megakaryocyte maturation and platelet production. Used to treat
thrombocytopenia.

Thrombopoietin is used to treat thrombocytopenia

Transplant Rejection

Hyperacute Rejection: Presence of preformed antibodies against the donors HLA or

ABO antigens at time of transplantation rejection of the transplant within
minutes
o The transplant must be immediately removed to prevent a severe systemic
inflammatory response. Hyperacute rejection can be avoided by
transplanting only tissue which is HLA or ABO-compatible with the patient

Acute rejection: Cytotoxic T cells react against a mis-matched HLA antigen or

MHCs

Usually occurs a week to a few months after transplantation because the T

cells take time to differentiate (cell-mediated immunity)

Treated with cyclosporine and muromonab-CD3 (OKT3)

Chronic rejection: Characterized by episodic bouts of rejection occurring months to

years after transplantation
o

Involves both humoral and cellular mechanisms which results in interstitial

fibrosis, vascular occlusion, loss of function. This type of rejection is
irreversible.

Graft vs. Host Disease: Common complication of allogeneic bone marrow

transplantation in which functional immune cells in the donor marrow recognize the
recipient as foreign and mount an immunologic attack against the recipient.
o

Common symptoms: jaundice, hepatosplenomegaly, diarrhea,

maculopapular rash