Immunodeficiency

Primary immunodeficiency inherited or acquired

Secondary immunodeficiency
Primary immunodeficiency
Range from often asymptomatic IgA deficiency to very rare conditions, but overall
not so rare
Can be presented during adult life
Before investigating for PID we have to exclude any secondary
immunodeficiencies
Classification
T and B cell deficiencies
Predominantly antibody deficiencies
Other well defined immunodeficiency syndromes
Diseases of immune dysregulation
Congenital defects of neutrophils number n function
Defects of innate immunity
Autoinflammatory syndromes
Defects of complement
Whom to be screened for PID?
Recurrent infections
Persistent infections
Unusually severe infections
Unususal or opportunistic infections
Autoimmunity / malignancy
T and B cell deficiency- SCID and CD40 deficiency
SCID- severe combined immunodeficiency
Defect in both humoral and CMI response
Susceptible for every type of infection ex; viral, bacterial, fungal, protozoal,
but mostly with p. jiroveci ( as severe interstitial pneumonia ) and candida
Early infancy- presents with severe diarrhea leading to FTT
Recurrent infections and opportunistic infections
Some forms-
X linked
Mutations of gene encoding common gamma chains of cytokine
receptors ( IL 2,4,7,9,15 )
IL-7 is a growth factor for expansion of T and B cells
Result combined deficiency of B and T cells
Another forms-
Mutations in adenosine deaminase enzyme
Diagnosis
FBC lymphocyte count < 2500/microl
Flowcytometry
Find evidence of T cell function- delayed type hs checking
Genetic analysis ( only for X linked SCID in SL )
Various subgroups of SCID
T absent/ B plus subgroup- no T cells and non functional B cells ( X
linked SCID )
T absent/ B absent subgroup ADA deficiency
T present/B absent omen syndrome
T present/B present
CD40L deficiency or hyper IgM syndrome
In normal immune response first occurring antibody is IgM, then it will
undergo isotope switching, and result production of other antibody types
like IgA, IgG, IgE
This isotope switching depends on
Interaction of CD40 on B cells andCD40L on T cells
Certain cytokines secreted by T cells
So when there is a mutation of CD40 or CD40L, no isotope switching, leads
to supranormal level of IgM and absent other antibodies
This is not a purely antibody deficiency there is also a defect in CMI, thats
why categorized in here
More susceptible for recurrent pyogenic and p.jirowesi inf.

Predominantly antibody deficiencies
1.Common variable immunodeficiency ( CVID )
Term for a heterogenous group of disorders with
Hypogammaglobulinemia
Impaired antibody response to vaccination
Increased infections
Clinically similar to X-linked agammaglobulinemia, but can see in both
males n females
Symptoms appear in second or third decade
Defect is variable
Mature B cells present but no plasma cells
Intrinsic B cell problem
Deficient T cell help to B cells
Increased risk for AI diseases
2.x-linked agammagolubilinemia
Failure of pre B cells to become mature B cells
Resulting absent gammaglobulin in blood
Mutations of bruton tyrosine kinase enzyme will arrest maturation of pre B
cell
Doesnt become apparent before 6 months, due to mothers antibodies
Increased risk of infections
By organisms which are cleared by antibody mediated phagocytosis-
staph. Aureus, strep. Pneu, hib
Certain viral inf enterovirus
Giardia lambia inf
XLA patients can clear virus, protozoa due to intact CMI
3.autosomal recessive agammaglobulinemia
4.specific IgA deficiency
major immunoglobulin in mucosal secretions
defends airway n GIT
most patients are asymptomatic, but increase risk for recurrent respiratory
tract infections and diarrhoea
5.specific antibody deficiency
6.hyper IgM syndrome
7.transient hypogammaglobulinemia of infancy moderate reduction of IgG and
IgA and normal B cells
8.subclass deficiency
Effects of antibody deficiency-
1. infections with capsulated bacteria like pneumococcus, Hib , N.
meningitides
2. recurrent ENT and res infections
3. infections from enteroviruses chronic encephalomyelitis
Assessment of antibody deficiency
immunoglobulin levels
subclasses ( IgG 1 -4 )
natural antibody isoaemagglutinins
response to protein antigens- tetanus
response to polysaccharides pneumococcal 23 valent and typhoid Vi
flowcytometry
molecular genetics
other well defined immunodeficiency syndromes
Occurrence of signs and features of PID in children with syndromes
1. Ataxia telangiectasia (AT)
neurodegenerative disease
poor co-ordination ( ataxia ) with small dilated blood vessels
reduce number of lymphocytes and impairment of lymphocyte function
2. Wiskott Aldrich syndrome (WAS)
X-linked recessive
Triad- eczema, thrombocytopenia and recurrent infections
First thymus is normal, but with aging depletetion of T lymphocytes in
blood and LN
3. digeorge syndrome
Developmental malformation of 3
rd
and 4
th
pharyngeal pouches
Leads to defects of thymus , parathyroid gland, and face
Cause deficient T cell maturation and absent T cells in blood n LN
B cell function is normal
4. Hyper IgE syndrome/ jobs syndrome
Deficient production of gamma IFN by T cells leads to abnormal neutrophil
chemotaxis

Diseases of immune dysregulation
PID where immune dysregulation and not infections are the main problem
1. Chediak higashi syndrome
Rare
Failure of phagolysosome formation leads to decreased phagocytosis
Cytotoxic T cells cant secrete toxic granules
2. gricelli syndrome
Deficiency in cytotoxic T cells
3. X-linked lymphoproliferative disease
Impaired activation of T and NK cells

Congenital defects of neutrophil number and function
Clinical manifestations
Non-superficial pyogenic infections
ENT and respiratory infections
Aspergillus and candida infections
Oral lesions ( periodontitis, ulcers )
Cellulitis without pus
Assessment of neutrophils
FBC dangerous if less than 1000/mm3, low in benign neutropenia, severe
congenital neutropenia, autoimmune neutropenia, cyclical and secondary
neutropenia
Blood picture giant granules in chediac higashi syndrome
Neutrophil function tests
o Chemotaxis- defective in gamma IFN receptor deficiency
o Adhesion- defective in LAD( leucocyte adhesion deficiency )
Deficiency of leucocyte adhesion molecules to the endothelial cells
They cant make their way out of the blood stream towards site of
infection
o Phagocytosis
o Oxidative burst defective in CGD ( chronic granulomatous disease )
Immune system is having a difficulty in forming reactive oxygen
compounds used to kill pathogens, which leads to formation of
granulomas in various organs.
o Intracellular killing
MSMD ( mendelian susceptibility to mycobacteria disease )
Can have disseminated disease with BCG and non tb mycobacteriae
Extraintestinal salmonella
Recurrent/ disseminated TB

Defects of innate immunity
Ex; ectodermal dysplasia with immunodeficiency,interleukin-1 receptor
associated kinase deficiency ( IRAK 4 ), chronic mucocutaneous candidiasis
Leads to recurrent ENT and respiratory disorders
Leads to pyogenic infections
But very rare condition
Autoinflammatory disorders
Familial Mediterranean fever ( FMF)
TRAPS
Complement deficiency
Rare
Recurrent infections with capsulated organisms

Microbes associated with particular PID



Treatment of immunodeficiency
Main two goals- minimize occurrence and impact of infection
Replace defective component
Antibody deficiency IV IG
Severe T cell deficiency stem cell transplantation

Secondary immune deficiency
1. Malnutrition
Vitamin A, riboflavin and pyridoxine changes in skin
Protein general atrophy of skin
Reduced cells , plasma cells decreased IgA in mucous membranes
Decreased phagocytosis , chemotaxis of PMN
Lymphopenia, decreased function decreased CMI
Preserved humoral immunity
2. DM
PMN- chemotaxis and phagocytosis reduced
Organism defect
BCG, salmonella, herpes and other
viruses, candida, cryptosporidiosis
CMI
Pneumococcus , Hib ,mycoplasma,
enteroviruses

antibody
Pneumococcus, Hib , meningococcus

COMPLEMENT
Staphylococcus, gram negatives ,
aspergillus, candida
neutrophil
Mycobacteria , salmonella MSMD
Increased bacterial and fungal infections of the skin, UTI, TB, candidiasis,
cellulitis
3. Protein losing states
Nephrotic syndrome infections commom ( with pneumococci )
4. splenectomy
Infections with capsulated infections
Severe infections with protozoa- babesiosis
5. Immunosuppressive drugs
Steroidos
Cyclophodphamide
Azathioprine
6. Malignancy
CLL
Hodgkins lymphoma decreased CMI
Non-hodgkins lymphoma both CMI and antibody
7.burns
8.uremia
9.ablation of lymphoid tissues.