Professional Documents
Culture Documents
• Example
– Familial hemophagocytic lymphohistiocytosis
– Immunodeficiency with hypopigmentation
• Susceptibility to infection and immune dysregulation
are associated in many primary immunodeficiency
diseases.
• Some primary immunodeficiencies cause immune
dysregulation in the absence of susceptibility to
infection.
• The common pathophysiological feature of familial
hemophagocytic lymphohistiocytosis (FHL) is an
impairment in cellular cytotoxicy.
• The clinical picture is one caused by an excessive
activation of the immune system and not by an
uncontrolled infection.
• Chediak-Higashi syndrome, Griscelli syndrome
II, Hermansky Pudlak syndrome II and p14
deficiency are autosomal recessive diseases
with oculocutaneous hypopigmentation and
variable signs of immunodeficiency.
– The molecular basis are defects in the biogenesis,
transport or delivery of secretory lysosomes,
leading to a risk of hemophagocytic
lymphohistiocytosis.
• X-Linked Lymphoproliferative syndrome (XLP)
has three main disease manifestations:
– fulminant infectious mononucleosis,
dysgammaglobulinemia and lymphoma.
– Disease onset is usually triggered by Epstein-Barr
virus (EBV)-infection and
– patients may be asymptomatic prior to EBV-
infection.
• Autoimmune lymphoproliferative syndrome
(ALPS) is a benign Lymphoproliferative disease
caused by defective apoptosis of peripheral
lymphocytes.
– The clinical hallmarks are lymphoproliferation and
autoimmune disease, in particular autoimmune
cytopenia.
• Typical manifestations of APECED (autoimmune
polyendocrinopathy with candidiasis and
ectodermal dystrophy) are chronic or recurrent
mucocutaneous candidiasis,
hypoparathyroidism and adrenocortical failure.
– The pathogenetic basis of APECED is a disturbed
development of immunological tolerance in the
thymus due to mutations in the gene encoding
AIRE (autoimmune regulator).
• Immunodysregulation, polyenocrinopathy,
enteropathy, X-linked (IPEX) is caused by
mutations in the gene “forkhead box P3”
(FOXP3), which is central for the generation
and function of regulatory CD4+T cells.
– IPEX usually manifests within the first year of life
with severe diarrhea, failure to thrive, eczematous
skin lesions, diabetes mellitus and/or other
endocrinopathies.
Autoimmune Polyendocrinopathy with
Candidiasis and Ectodermal Dystrophy
(APECED)
• APECED also called Autoimmune Polyendocrine syndrome
Type I (APS-I), is an autosomal recessive disorder of immune
regulation.
• The disease is characterized by multi-organ autoimmunity
leading to chronic mucocutaneous candidiasis (CMC),
hypoparathyroidism and adrenocortical failure as the most
common phenotypic manifestations.
• The genetic basis of APECED are mutations in the gene
encoding AIRE (autoimmune regulator).
• Lack of AIRE expression allows these self-reactive T cells to
escape thymic deletion and these cells then cause the typical
multi-organ autoimmunity in the periphery.
Clinical Manifestations
• In the majority of patients, the first symptom
is recurrent mucocutaneous candidiasis, which
is frequently difficult to treat.
• It usually presents as oral or nail disease, but
may also manifest with substernal pain on
swallowing as isolated esophageal candidiasis.
• It is possible that it reflects an element of
ectodermal dysplasia, which locally facilitates
the establishment of candida infection.
• The most frequent manifestation of ectodermal
dysplasia is enamel hypoplasia of permanent teeth.
• The first endocrine manifestation of APECED is usually
hypoparathyroidism that often manifests before
school-age.
• Vitiligo and urticarial rashes frequently associated with
fever.
• Gastrointestinal complaints include autoimmune
hepatitis, chronic diarrhea and pernicious anemia due
to antiparietal cell or intrinsic factor antibodies,
keratoconjunctivitis and tubulointerstitial nephritis
were also reported.
5. Defects in innate immunity:
receptors and signaling components
• The innate immunity is the first line of defense
against pathogens, exerting fast and effective
responses via preformed receptors.
• Toll-like receptors (TLRs) recognize specific
molecular patterns found in a broad range of
microbial pathogens such as bacteria and
viruses, triggering inflammatory and antiviral
responses, which result in the eradication of
invading pathogens.
• Primary immunodeficiency diseases with primary
defects in TLR signaling include Interleukin-1
receptor-associated kinase-4 (IRAK-4) deficiency,
UNC-93B deficiency and TLR3 deficiency.
• These defects predispose patients to a narrow
range of infections; pneumococcal infections in
IRAK-4 deficiency, and herpes simplex
encephalitis in UNC-93B and TLR3 deficiencies.
• Anhidrotic ectodermal dysplasia with
immunodeficiency is caused by defects in the
nuclear factor NF-κB signaling. In these
disorders, TLR signaling is also impaired.
• Poor inflammatory response despite severe
infection and absence of fever are
characteristic of TLR defects.
anhidrotic ectodermal dysplasia
• Mendelian susceptibility to mycobacterial diseases are
characterized by recurrent and severe infections
caused by weakly virulent organisms, such as
environmental mycobacteria and Bacille Calmette-
Guerin, and is associated with impaired IL-
12/Interferon-γ dependent innate immunity.
• WHIM (warts, hypogammaglobulinemia, infections,
myelokathexis) syndrome is a primary
immunodeficiency disease caused by mutation of the
CXCR4 chemokine receptor gene. Both innate and
adaptive immunity are impaired in this disorder.
• Epidermodysplasia verruciformis is a rare
autosomal recessive disorder associated with
a high risk of skin carcinoma that results from
an abnormal susceptibility to infection by
specific human papillomaviruses (HPVs).
Epidermodysplasia verruciformis
Defective Toll-Like Receptor (TLR)
Signaling with Ectodermal Dysplasia
• XL- and AD-Anhidrotic Ectodermal Dysplasias
with Immunodeficiency.
• Impaired NF-κB activation by ectodysplasin in
skin and altered RANK (receptor activator of NF-
κB)-Ligand signaling in bone cells have been
observed in ectodermal dysplasia (EDA).
• EDA is a unique feature of defects of NF-κB
activation due to altered NEMO (Nuclear Factor-
kappa-B Essential Modulator)that is not observed
in other disorders of TLR signaling.
• The NEMO (IKBKG) gene encodes a protein of 419
amino acids. This protein is an essential part of
the IKK complex and consists of two N-terminal
coiled coil domains followed by a leucine zipper
and C-terminal zinc finger, all separated by α-
helical regions.
• X-linked anhidrotic ectodermal dysplasia with
immunodeficiency (EDA-ID) is a rare inherited
disease caused by hypomorphic mutations in the
gene encoding NEMO.
The NF-κB signaling
pathway.
In response to multiple
stimuli, IKK kinase
(composed of IKKα, IKKβ
and NEMO) is activated.
IKK phosphorylates NF-
κB inhibitor (IκBα),
leading to its degradation
by proteasome and
release of NF- κB
(p50/p65) dimer. NF-κB
translocates into the
nucleus, where it
regulates the expression
of hundreds of genes.
The activation of NF-κB
through TLRs .
• There is abnormal development of ectodermal derived
structures with nail abnormalities, hypotrichosis,
hypohidrosis, and hypodontia with conical incisors.
• Patients are susceptible to severe bacterial infections
of the respiratory and gastrointestinal tracts, skin, soft
tissues and bones, and suffer from meningitis and
septicemia during infancy.
• Infections caused by weakly pathogenic mycobacteria,
such as Mycobacterium kansasii, Mycobacterium
avium, and Mycobacterium bovis, are typical in these
patients (MSMD).
Mendelian Susceptibility to Mycobacterial
Diseases
• The IL-12/Interferon-γ dependent signaling
pathway is central to controlling mycobacterial
infections.
• Molecular defects in IL-12/IFN-γ dependent
signaling cause rare genetic disorders.
• Theses defects belonging to the group of
Mendelian susceptibility to mycobacterial
diseases (MSMD) are characterized by
disseminated or localized infections caused by
either environmental mycobacteria (EM) or BCG
vaccines, in otherwise healthy individuals.
IFN-γ and IL-12 signaling pathway
in immunity against mycobacteria
and some other intracellular
organism. Structures affected in
MSMD are marked in gray. MB
mycobacteria.
• RC-IFN-γR-deficient patients are most
susceptible to severe, early onset
mycobacterial infections with profoundly
impaired granuloma formation.
• In contrast, patients with partial IFN-γR
deficiencies acquire mycobacterial infections
later in life, still sprout granulomas, and are
likely to respond well to antimycobacterial
antibiotics.
• These bacteria can also sometimes be found
at sites of infections without doing much
harm, e.g., at teeth.
Warts, Hypogammaglobulinemia,
Infections, Myelokathexis ( WHIM)
Syndrome
• The WHIM syndrome is comprised of warts,
hypogammaglobulinemia, infections, and
myelokathexis.
• WHIM syndrome is caused by heterozygous
mutations in the gene coding for the
chemokine receptor CXCR4 (chemokine, CXC
motif, receptor 4).
• A specific susceptibility to HPV-induced warts,
which most often appear in the second decade of
life, is characteristic, but the warts may occur
earlier as well in some extensive cutaneous
verrucosis, including genital condyloma
acuminata with dysplastic changes appears.
• Patients present with recurrent bacterial
infections from infancy including pneumonia,
sinusitis, otitis, cellulitis, periodontitis, and
abscesses.
6. Autoinflammatory disorders
• Autoinflammatory disorders constitutes a new
term that covers a group of diseases
characterized by recurrent generalized
inflammation in the absence of infectious or
autoimmune causes.
• Dysregulation of the innate immune system
causes inflammation by affecting the pathways
connected to the NOD-like receptors.
• The patients are at risk of developing
amyloidosis, the main long-term sequelae of
many of these disorders.
• The term was initially used only for the inherited
periodic fever syndromes.
• Over the past few years, the concept of
autoinflammatory disorders has expanded to
encompass an increasing number of polygenic/
multifactorial diseases.
– Familial Mediterranean fever (FMF)
– Blau syndrome
– TNF receptor-associated periodic syndrome (TRAPS)
• Common symptoms, during attacks, in
autoinflammatory diseases are malaise, fever,
arthritis/arthralgia, abdominal pain and skin rash.
• The patients also have an inflammatory reaction
during the attack.
• Onset of the disease is generally noted during
childhood or adolescence.
• The patients are usually symptom-free between
attacks but may have a subclinical inflammation.
Mevalonate Kinase Deficiency (MKD)
(Hyperimmunoglobulinemia D and Periodic
Fever Syndrome, Mevalonic aciduria)
• Increased IgD and periodic fever.
• MKD is an uncommon inborn error of the
cholesterol biosynthesis.
• MKD is autosomal recessive inherited and caused
by a mutation in the mevalonate kinase (MVK)
gene located on chromosome 12.
• There is also an increased production of IL-1β in
HIDS and anecdotal effect of anakinra, an IL-1
blocker.
• The symptoms usually start appearing before the
age of 1 year and are characterized by episodes
of fever and inflammation that recur every 2–8
weeks and last 3–7 days.
• Other common symptoms during attacks are skin
rash, cervical lymphadenopathy,
arthritis/arthralgia, diarrhea and abdominal pain.
• Sometimes there are hepatomegaly and oral or
genital ulcers.
Pyogenic Arthritis, Pyoderma
Gangrenosum and Acne Syndrome (PAPA)
• PAPA is an autosomal dominant inherited disease
characterized by pyogen arthritis, pyoderma
gangrenosum and acne.
• caused by a mutation in the CD2- binding protein
1 (CD2BP1) (= proline serine threonine
phosphatase interacting protein 1, PSTPIP1) gene
on chromosome 15.
• the CD2BP1 protein binds to pyrin, the protein
affected in FMF (familial Mediterranean fever),
and may cause inflammation in the same
pathway of the innate immune system as FMF.
• The first manifestation to appear, between 1
and 16 years of age, is usually oligoarticular
pyogenic arthritis.
• Acne develops later, often at puberty. The
acne is often severe and cystic. Pyoderma
gangranosum-like ulcerative lesions occurs in
some patients.
Periodic Fever, Aphtous Stomatitis, Pharyngitis
and Cervical Adenitis (PFAPA)
• an increase of pro-inflammatory mediators, even
between febrile attacks, suggesting dysregulation
of the immune response in PFAPA syndrome, with
continuous proinflammatory cytokine activation
(IL-1β, IL-6 and TNF-α) and a reduced anti-
inflammatory response (IL-4).
• The recurrent febrile attacks have an interval of
2–8 weeks and the duration is usually 3–7 days.
• The fever is accompanied by pharyngitis, cervical
adenitis and/or oral aphthae.
Behçet’s Disease (BD)
• BD is a chronic relapsing inflammatory disease
that has been suggested to be included
among the autoinflammatory syndromes.
• The manifestations are oral and genital ulcers,
folliculitis, erythema nodosum and uveitis.
7. Complement deficiencies
• Complement plays a role in the recognition,
opsonization, and killing or clearance of invading
microorganisms, immune complexes and altered
host cells.
• There are three main pathways of complement
activation:
– the classical pathway (C1 dependent),
– the lectin route (mannan-binding lectin/ficolin and
MASP dependent), in which both C4 and C2 play a
role, and
– the alternative pathway (Factor B, D, and properdin
dependent).
• Complement deficiencies are two types; acquired
or hereditary.
• Acquired deficiency may be caused by infection
or immune-complex disorders.
• Most inherited deficiencies of complement
components are expressed in autosomal
recessive patterns, whereas properdin deficiency
is X linked. The gene defects may give rise to a
dysfunctional protein or to complete absence of
the protein.
• Primary complement deficiencies are in
particular associated with increased
susceptibility to recurrent and invasive
infections and with autoimmune disorders.
• Deficiency of C1 inhibitor (C1INH), themain
inhibitor of the classical and lectin pathways
of complement activation, leads to
angioedema.
• deficiency of an early complement component
in any of the activation pathways, leads to
decreased activation of C3, manifested with
recurrent pyogenic infections, principally with
encapsulated bacteria such as Streptococcus
pneumoniae and Haemophilus influenza type-
b, because opsonization followed by
phagocytosis is the main host defense against
these organisms
• For deficiencies of terminal complement
components (C5-9), recurrent systemic neisserial
infection is the dominant manifestation, because
clearance of these bacteria depends on C5b-9-
mediated lysis.
• Autoimmune, systemic lupus erythematosus (SLE)
like diseases are associated with deficiencies of
many complement components, but are typically
seen with classical pathway component
deficiencies, in particular with C1q deficiency
• MBL deficiency occurs frequently and acts as a
disease-modifying factor. All other complement
deficiencies are rare and result in recurrent
pyogenic infections or autoimmune disease
reminiscent of systemic lupus erythematosus.
• C1INH (C1 inhibitor) replacement therapy is
available for hereditary (or acquired) angioedema
(HAE), and replacement therapy is being
developed for MBL (mannan-binding lectin).
• Complement-targeted therapy (e.g., C1INH,
soluble CR1, antibodies against C5, C5aR
antagonists) will become important in the
near future for adjuvant treatment in
ischemia-reperfusion injury, transplantation
medicine, and inflammatory disease.
Example
• Deficiencies of classical pathway components
– C1q/r/s deficiency
• Deficiencies of lectin pathway components
– MBL deficiency
• Deficiencies of terminal pathway components
– C5/6/7/8/9 deficiency
8. Other well-defined immunodeficiencies