congenital immunodeficiencies
Sourcies:
FA step 1 (2010), FA step 2 (2012), MTB CK, Step-Up to USMLE Step 2 (2007)
B-cell disorders
•Bruton’s agammaglobulinemia
•Hyper-IgM syndrome
•Selective Ig deficiency
•Common variable immunodeficiency (CVID)
T-cell disorders
•Thymic aplasia(DiGeorgesyndrome)
•IL-12 receptor defi ciency
•Hyper-IgE syndrome/Job’ssyndrome (Phagocyte dysfunction)
•Chronic mucocutaneous candidiasis
B and T cell disorders
•Severe combined immunodeficiency(SCID)
•Ataxia-telangiectasia
•Wiskott-Aldrich syndrome
Phagocyte dysfunction
•Leukocyteadhesion deficiency (type 1)
•Chédiak-Higashi syndrome
•Chronic granulomatous disease
Complement Disorders
•C1 esterase deficiency (hereditary angioedema)
•Terminal complement deficiency (C5-C9)
B-cell disorders
B cells: make immunoglobulins and are responsible for immunity against
extracellular bacteria.
B-cell deficiencies represent 50% of all congenital immunodeficiencies.
Presents after 6 months of age with recurrent sinopulmonary, GI, and
urinary tract infections with incapsulated organisms (H. Influenzae, S.
pneumoniae, N meningitidis). Treat with IVIG (except IgA deficiencies.)
•Bruton’s agammaglobulinemia
•Hyper-IgM syndrome
•Selective Ig deficiency
•Common variable immunodeficiency (CVID)
Bruton’s agammaglobulinemia X-linked recessive
Description:
↑in Boys; Defect in a bruton’s tyrosine kinase (BTK) gene →blocks B-cell
differentiation/maturation; absence of the tonsils, adenoids,
lymphnodes (if present, germinal centers are missing).
Recurrent sinopulmonary encapsulated bacterial (Pseudomonas, S. pneumoniae,
Hemophilus) infections after 6 months (↓ maternal IgG) due to opsonization
defect.
Diagnosis:
Normal pro-B
↓number of matured B cells (<2% CD19+B cells; normal 18-47%), and
increased T cells
↓immunoglobulins of all classes
Treatment:
IVIG, prophylactic/appropriate antibiotics, supportive pulmonary care
Bruton’s congenital agammaglobulinemia can be confused with transient
hypogammaglobulinemia of infancey(THI
is characterized by low IgG, variable
IgM and normal IgA but normalize by 6-11 months), as both are characterized
by increase susceptibility to infections at 6-9 months of age. B cells are decreased
in Bruton’s, whereas they are normal in THI.
Hyper-IgM syndrome
Description:
Defective CD40L(ligand) on helper T cells resulting in poor interaction with B
cells and inability to classswitch.
Severe pyogenic infections early in life.
Diagnosis:
↑IgM;↓IgG, IgA, IgE
possible decreased Hgb, Hct, platelets, and neutrophils
Treatment:
IVIG, prophylactic antibiotics; bone marrow transplant
Selective Ig deficiency / IgA deficiency
Description:
Failure of B cells to mature into plasma cells, abnormal immune globulin
production by B cells;
Defect in isotype switching→ deficiency in specific class of immunoglobulins.
Ig A deficiency is most common and is assosiated with atopic disease
(dermatitis or asthma), sinus, gastrointestinal and lung infections; milk
allergies, anaphylaxis on exposure to blood products with IgA; spruelike
condition with fat malabsorption, increased in the risk of vitiligo, thyroiditis, and
rheumatoid arthritis.
Diagnosis:
Quantitative immunoglobulin levels show decreased IgA <50 mcg/ml (normal
IgA is 76-390 mg/dl) with normal levels of other immune globulins
Treatment: Prophylactic antibiotics; IVIG with caution (small risk of
anaphylaxis)
Common variable immunodeficiency (CVID)
Aquired hypogammaglobulinemia
Description:
Can be acquired in 15s–35s; many causes.
Defect in B-cell maturation/differentiation resulting in low immune
globulin levels.
patients experience increased pyogenic upper and lower
respiratory and gastrointestinal(spruelike) infections beginning in
second decade of life;
associated with increased risk of malignant neoplasms
(lymphoma) and autoimmune disorders (pernicious anemia
and seronegative rheumatic diseases)
Diagnosis: age (15s–35s)
Normal number of B cells; ↓ plasma cells, and ↓ all Ig levels.
poor response to vaccines; decreased CD4:CD8 T-cell ratio;
Treatment: IVIG, appropriate antibiotics
Bruton’s and CVID aslo have similar symptoms; but the Bruton’s is
found in boys ~6 months of age whereas CVID is seen in older males
and females, and symptoms are less sever. CVID has normal
number of circulating B cells.
T-cell disorders
T cells: responsible for immunity against intracellular bacteria,
viruses, and fungi.
T-cell deficiencies tend to present earlier (1-3 months) with
opportunistic and low-grade fungal, viral, and intracellular bacterial
infections (mycobacteria). Secondary B-cell disfunction may also be
present.
•Thymic aplasia(DiGeorgesyndrome)
•IL-12 receptor defi ciency
•Hyper-IgE syndrome (Job’ssyndrome)
•Chronic mucocutaneous candidiasis
Thymic aplasia(DiGeorge syndrome)
Description:
Chromosomal deletion in 22q11, failure to develop 3rd and 4th pharyngeal pouches
resulting in thymic and parathyroid hypoplasia, abnormal facial structure,
tetany/seizures (hypocalcemia) in the first days of life, recurrent viral/fungal(PCP)
infections (T-cell deficiency), congenital heart and great vessel
anomalies(transposition of the vessels), cleft palate, esophageal atresia,
mandibular hypoplasia, notched and low set ears
Diagnosis: ↓ T cells,↓ PTH,↓ Ca2+
Absent thymic shadow on CXR, delayed hypersensitivity skin test, genetic screening
can detect chromosomal abnormality
Treatment: Calcium, vitamin D, thymic transplant, bone marrow transplant,
surgical correction of heart abnormalities; IVIG or prophylactic antibiotics may be
helpful.
IL-12 receptor deficiency
Description:
IL-12 (T cell-stimulating factor) is secreted by B cells and macrophages and is involved
in the activation of NK and differentiation of naive T cells into Th1 cells. It stimulates
the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α)
from T and natural killer (NK) cells, and reduces IL-4 mediated suppression of IFN-γ.
↓ Th 1 response cause disseminated mycobacterial infections.
Diagnosis: ↓ IFN-γ.
Hyper-IgE (Job’s) syndrome AD
”Phagocytic Cell Disorders”
Description:
The most common mutations is splice site on chromosome 17’s longer arm in Stat3
gene. Th cells fail to produce IFN-γ causing inability of neutrophils to respond to
chemotactic stimuli, T-cell signaling, and overproduction of IgE resulting in
chronic dermatitis (eczema), recurrent cold (noninflamed) abscesses, coarse
facies, retained primary teeth, pulmonary, skin and joint infections with S. aureus and
bone fractures.
Diagnosis:
↑ IgE, eosinophilia; defective chemotactic response of neutrophils on stimulation
Treatment:Penicillinase-resistant antibiotics and IVIG
Chronic mucocutaneous candidiasis
Description:
T-cell dysfunction causing persistent infection of skin, mucous membranes, and
nails by Candida albicans; frequent associated adrenal pathology (insufficiency)
Diagnosis:
Poor reaction to cutaneous C. albicans anergy test; possible decreased IgG
Treatment: Antifungal agents (fluconazole)
B and T cell disorders
•Severe combined immunodeficiency(SCID)
•Ataxia-telangiectasia
•Wiskott-Aldrich syndrome
Severe combined
immunodeficiency
(SCID)
Description:
Severe lack of B, T and NK cells due to a defect in stem cell maturation.
Several types: defective IL-2 receptor (most common, X-linked), adenosine deaminase
deficiency (AR), failure to synthesize MHC II antigens.
Absent T cells and abnormal antibody function resulting in severe immune
compromise; patients experience significant recurrent infections by recurrent viral,
bacterial, fungal, and protozoal; fatal at an early age.
Diagnosis:
Significantly decreased WBCs, decreased immune globulins, absent thymic shadow
on chest x-rays.
Treatment:
IVIG, antibiotics, bone marrow transplant (no allograft rejection); no live or
attenuated vaccines should be administered, Requires PCP prophylaxis.
Ataxia-telangiectasia - AR
Description:
Defect in DNA repair enzymes.
Progressive cerebellar ataxia, oculocutaneous telangiectasias, increased
incidence of malignancies (non-Hodgkin’s lymphoma, leukemia and gastric
carcinoma), and impaired WBC and IgA development
Diagnosis:
cerebellar defects(ataxia), Spiderangiomas(telangiectasia) develop after 3 yr of age;
recurrent pulmonary infections begin a few years later; decreased WBCs & IgA
Treatment:
IVIG and prophylactic antibiotics may be helpful, but treatment usually unable to limit
disease progression
Wiskott-Aldrich syndrome X-linked recessive
Description: thrombocytopenia, eczema and infections with encapsulated germs
Mutated Wiskott-Aldrich syndrome protein (WASP) gene which is mainly expressed in
hematopoietic cells. The platelets are small and do not function properly and are
removed by the spleen; In T-cell, WASp is activated via T-cell receptor (TCR) signaling
pathways to induce cytoskeleton rearrangements during immunological synapse.
The immune deficiency is also caused by decreased antibody production.
Initial manifestations often present at birth and consists of easy bleeding
(petechiae/purpura), bruises, bleeding from circumcision and blood in stool, eczema
and recurrent otitis media, lymphoma/leukemia, infection from encapsulated
organisms (Hib), S. phneumoniae, S. aureuse.
Diagnosis:
Genetic analysis detects abnormal WASP gene, ↓IgM ↑IgE, IgA; and thrombocytopenia
and low T cells, poor antibody responses to polysaccharide antigens.
Treatment:
Splenectomy, antibiotic prophylaxis, IVIG and bone marrow transplantation
Phagocyte dysfunction
Phagocyte deficiencies are characterized by
mucus membrane infections, abscesses, and poor
wound healing. Infections with catalase „+“
organizms, fungi, and gram „–” enteric organisms
are common.
•Leukocyteadhesion deficiency (type 1,2)
•Chédiak-Higashi syndrome
•Chronic granulomatous disease
Leukocyte adhesion deficiency (type 1, 2) AR
Description: Inability of neutrophils to leave circulation because of abnormal
leukocyte LFA-1 integrin/CD18 (type 1) or E-selectin (type 2);
Recurrent bacterial infections, omphalitis, delayed separation of umbilicus, absent
pus formation and minimal inflimation in wound.
recurrent bacterial infections of upper respiratory tract and skin; short stature,
abnormal facies, and cognitive impairment seen in type 2 disease
Diagnosis:
Neutrophilia w/out molymorphs in the infected tissue or pus; defective
chemotactic response of neutrophils upon stimulation.
Treatment:
Prophylactic antibiotics; bone marrow transplant.
Chédiak-Higashi syndrome - AR
Description:
defect in microtubular function with ↓ phagocytosis, ↓degranulation, ↓chemotaxis.
Recurrent pyogenic infections by Staphylococci aureus, Streptococcus pyogenes and
Pseudomonas species; partial oculocutaneous albinism, peripheral and cranial neuropathy,
hepatosplenomegaly, progressive lymphoproliferative syndrome, pancytopenia (abnormal
platelets and neutropenia)
Diagnosis:
Look for giant granules in neutrophils.
Treatment:
Prophylactic antibiotics (trimethoprim-sulfamethoxazole), bone marrow transplant
Chronic granulomatous disease
Description:
An X-linked (2/3) or autosomal recessive (1/3) disease with dysfunction of the
NADPH oxidase enzyme complex in phagocytic cells (PMNs and macrophages)
causing absent respiratory burst. Neutrophils cannot digest engulfed bacteria.
Infecting organisms are catalase + (S. aureus, E. coli, Candida, Klebsiella,
Pseudomonas, Aspergillus). Anemia, osteomyelitis, lymphadenopathy(lymph
nodes w/purulent material leaking out), hypergamaglobulinemia, pulmonary,
cutaneous and visceral (Liver) abscess formation may be present,
hepatospleenomegaly, anemia of chronic disease, gingivitis, and
dermatitis. May have granulomas of the skin and GI/GU tracts, aphthous
ulcers (pinful mouth ulcers)
Diagnosis:
Negative NitroBlue tetrazolium dye reduction test.
Treatment:
Daily TMP-SMX; IFN-γ can decrease incidence of
serious infections; Bone marrow transplantation.
Complement Disorders
Complement deficiencies present similarly as pt w/congenital asplenia or
splenic dysfunction (sickle cell disease). Characterized by recurrent bacterial
infection with encapsulated organisms.
• C1 esterase deficiency (hereditary angioedema)
• Terminal complement deficiency (C5-C9)
C1 esterase deficiency (hereditary angioedema) AD
C1 esterase prevent spontaneous activation of the complement system by C1.
Description: An autosomal dominant disorder with recurrent episodes of angioedema
lasting 2-27 hours and is provoked by stress or trauma. Can lead to lifethreatening airway
edema.
There are three types of C1 inhibitor deficiency:
Type I: Hereditary. Three of the four genes for C1 inhibitor are absent, leading to low levels
of C1 inhibitor.
Type II: Hereditary. There are high levels of C1 inhibitor, but it is non-functional.
Type III: Hereditary or acquired. Related to hormone levels in the body.
Diagnosis:
symptoms resemble those of more common disorders, such as allergy. An important clue
is the failure of hereditary angioedema to respond to antihistamines or steroids, a
characteristic that distinguishes it from allergic reactions.
Only a laboratory analysis can provide final confirmation. In this analysis, it is usually a
reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected.
Total hemolytic compliment (CH50) to assess the quality and fanction of compliment.
Treatment:
Purified C1 esterase and FFP can be used prior surgery.
In hereditary angioedema, bradykinin formation is caused by continuous activation of the
complement system due to a deficiency in one of its prime inhibitors, C1-esterase (C1-inhibitor
or C1INH), and continuous production of kallikrein.
ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin.
Terminal complement deficiency (C5-C9)
Description:
Inability to form membrane attack complex (MAC). Pt presents with recurrent
Neisseria infections, meningococcal or gonococcal. Rarely associated with lupus
or glomerulonephritis.
Diagnosis:
Total complement activity (CH50 or CH100) may be ordered to look at the
integrity of the entire classical complement pathway; then analysis of the
individual components may be warranted.
Treatment:
Meningococcal vaccine and appropriate antibiotics.
congenital immunodeficiencies
B-cell disorders
•Bruton’s agammaglobulinemia- no tonsils/germinal centers, Normal pro-B, <2% CD19+B cells, increased T cells, ↓all Igs
•Hyper-IgM syndrome - CD40L, classswitching,↑IgM;↓Hgb, Hct, platelets, and neutrophils
•Selective Ig deficiency - isotype switch, atopic disease(dermatitis,asthma), milk allergies, IgA anaphylaxis, vitiligo, thyroiditis, RA
•Common variable immunodeficiency (CVID) - pernicious anemia, seronegative RA, 15s–35s, low CD4/CD8, Normal B cells
T-cell disorders
•Thymic aplasia(DiGeorgesyndrome) – pouches, tetany/seizures, heart(TGV), esophageal atresia, notched and low set ears
•IL-12 receptor defi ciency- disseminated mycobacterial, Tx: ↓ IFN-γ
•Hyper-IgE (Job’s) syndrome – no IFN-γ, high IgE, eosinophilia, dermatitis, cold abscesses, primary teeth, bone fractures
•Chronic mucocutaneous candidiasis – adrenal insufficiency, Tx: low IgG, Poor reaction to C. albicans anergy test
B and T cell disorders
•Severe combined immunodeficiency(SCID) - absent thymic shadow, abnormal/low antibody, IL-2 (XR), AA (AR)
•Ataxia-telangiectasia – malignancies, spiderangiomas, low IgA & WBC, pulmonary infections
•Wiskott-Aldrich syndrome – thrombocytopenia(circumcision), eczema, antibody, otitis, cancer, low IgM, Tx: Splenectomy
Phagocyte dysfunction
•Leukocyteadhesion deficiency (type 1) – umbilicus, absent pus, infected tissue w/out molymorphs (minimal inflimation)
•CHédiak-Higashi syndrome – albinism, neuropathy, granules in neutrophils, Hepatosplenomegaly
•CHronic granulomatous disease - catalase+, lymphadenopathy, Liver abscess, aphthous ulcers, Hepatosplenomegaly
Complement Disorders
•C1 esterase deficiency (hereditary angioedema) – airway edema, reduced C4
•Terminal complement deficiency (C5-C9) - Neisseria, lupus or glomerulonephritis, Tx: Meningococcal vaccine