Primary Immunodeficiency Flashcards
Top 6 antibody defiencies
- Agammaglobuinemia (x-linked and AR) 2. Hyper-IgM Syndrome 3. IgA deficiency 4. Common variable immunodeficiency 5. Specific antibody deficiency 6. Transient hypogammaglobulinemia of infancy
Agammaglobulinemias
Caused by defects in B-cell development. Germinal center formation in these patients is defective (underdevelopment of lymphoid tissues, lymph nodes, peyer’s patches, spleen, tonsils, adenoids)
Enzyme associated in lyonized boys/females with agamaglobulinemias?
B cell tyrosine kinase
Mode of inheritance for agammaglobulinemia?
85% x-linked
Role of BTK?
Associated with pre-B cell receptor and is required for transducing signals downstrream=Stimulate B-cell maturation
Characterisitics of X-linked agammaglbulinemia
Approximately half are due to positive family history. IgG is usually<100 mg/dl; B-cells<2% of lymphocytes (usually 0.05-0.3%), and NORMAL T-CELL FUNCTION AND NUMBER
Hyper-IgM Syndrome characteristics
Defects in B-cell isotype switching. Normal numbers of B-cells, but express elevated levels of IgM with low IgG, IgE, and IgA
Mutant proteins in Hyper-IgM syndrome
CD40, CD40L, IKK-gamma (NEMO), AID, UNG
IgA Deficiency Characteristics
Most common primary immunodeficiency (1:500 healthy blood donors); IgA<5-7 mg/dl; Usually asymptomatic (occasionally increased sinopulmonary infections, diarrhea, autoimmune disease
Common Variable Immunodeficiency characteristics
2nd most frequent PID in humans after IgA. Most prevalent PID. Recurrent infections (sinusitis most common followed by pneumonia, life threatening infections). Granulomatous disease, autoimmune disorders, splenomegaly, and certain malignancies (300x LYMPHOMA RISK), REDUCED SERUM IgG, IgA, and/or IgM, Abset or impaired specific antibody responses to previous infection or vaccination
Specific antibody deficiency
Recurrent sinopulmonary infections; Normal IgG, IgA, IgM; Normal B-cell number and Normal T-cell number and function; Impaired vaccine response (polysaccharide); Impaired antibody response to natural infection with encapsulated bacteria
Encapsulated organisms
Streptococcus pneumoniae and pyogenes; Staph aureus; Klebsiella; Haemophilus influenzae; Pseudomonas aeruginosa; Neisseria menigngitidis; Cryptococcus neoformans (Mycoplasma, bordetella pertussis, some e coli, streptococcus agalactiae, Yersinia Pestis (F1 envelope)
Transient Hypogammaglublinemia of infancy
Recurrent sinopulmonary infections, low IgG, NORMAL SPECIFIC ANTIBODIES, normal lymphocyte number and function, delay in maturation of T-cell help for antibody production, Onset of about 6 months of age, resolve by age 4
Types of SCID And Lymphocyte development deficiencies
- Adenosine deaminase deficiency (worst case)/PNP Deficiency 2. Gamma-c? Deficiency 3. DiGeorge syndrome 4. RAG Deficiency
Mode of inheritance Adenosine deaminase deficiency; step involved
autosomal; stem cell to pro-B cell AND stem cell to Pro-T-cell
Mode of inheritance PNP Deficiency; step involved
autosomal; stem cell to pro-B cell AND stem cell to Pro-T-cell
Mode of inheritance RAG deficiency; step involved
autosomal; Pro-B cell to Pre-B cell AND Pro-Tcell to Pre-T cell
Mode of inheritance with gamma c deficiency; step involved with gamma c and digeorge syndrome
X-linked; Stem cell to pro-t cell
Omenn syndrome characteristics
Hypomorphic mutations (most common in RAG genes); Low to normal number of T-cells but oligoclonal T-cell population; early onset (<3 months) of a diffuse exudative erythroderma; lymphadenopathy; hepatosplenomegaly; chronic persistent diarrhea; failure to thrive; elevated IgE and eosinophili (can be confused with normal baby eczema); “leaky SCID”
Digeorge syndrome characteristics
Defect in embryogenesis 3rd and 4th pharyngeal pouches. Most have deletion of chromosome 22q11.2. Dysmorphic faces (micrognathia, low set ears), hypocalcemia (lack of parathyroids, hypoplastic to aplastic thymus, congenital heart disease (aortic defects, VSD), presents in first few days of life. Affects both males and females
Diagnosing of digeorge syndrome
Diagnosed immediately by lateral chest x-ray (absence of thymic shadow)
Partial DiGeorge Syndrome
More frequent; thymic hypoplasia (normal corticomedullary differentiation, presence of Hassall’s corpuscles, normal thymic function); CD4 cells>400/mm3; T-cell function adequate, B-cell numbers and function normal, usually free of infections
Complete Digeorge Syndrome
Uncommon; thymic apalsia, CD4 cells<400mm3, B-cells numbers normal; antibody response decreased; susceptible to infections; susceptible to GVHD
Wiskott Aldrich Syndrome
Eczema; THROMBOCYTOPENIA WITH SMALL PLATELETS (look for low MPV); immunodeficiency; Inovlved with actin polymerization
Types of lymphocyte mitogen proliferation assays
Nonspecific mitogens phytohemagglutin (PHA), concanavalin (Con A), and pokeweek determined by 3H-thymidine incorporation
Chronic granulomatous disease
Recurrent bacterial infection with catalase positive organisms (staph, serratia, aspergillus); pathognomic organism (chromobacterium violaceum), granulomas of skin, liver, lungs, lymph nodes, phagocytic cells ingest but do not kill bacteria due to failure to form oxygen radicals
Gene defects in CGD
Gene defects interruprs electron transfer necessary to produce superoxide. GP91 phox (XL), p22 phox (AR), p47 (AR), p67 (AR)
Diagnosing CGD
1 Nitroblue tetrazolium dye test, 2. superoxide radical formation (chemiluminescene test). 3. Flow cytometry (dihydorhodamine 123 assay)
Leukocyte adhesion deficiency-1
Absent beta subunit (CD18) of 3 cell surface glycoproteins (CD11 family) B2 integrins, Neutrophils CANNOT MIGRATE toward inflammatory stimuli or ADHERE to vaascular endothelium
Diagnosis of Leukocyte adhesion deficiency-1
Recurrent soft tissue infections, DELAYED UMBILICAL CORD SEPARATION, severe periodontal disease, No pus formation despite high white blood counts
Hyper IgE syndrome (Job syndrome)
Recurrent staphylococcal abscesses, sinopulmonary infections, and severe eczema; retained primary teeth; recurrent candida; recurrent bone fractures; very elevated IgE level >2000, peripheral eosinophila
Diagnosis of Primary Immunodeficiency
Birth to 3 months (phagocytic cell defects, complement defects, digeorge syndrome); 3 to 6 months (severe combined immunodicieincy SCID); 6 to 18 months (X-linked agammaglobulinemia, transient hypogam); 18 months through adulthood (common variable immunodeficiency, complement defects
Treatment for combined immunodeficiency
stem cell transplant, enzyme replacement (PEG-ADA), thymic transplant for digeorge, gene therapy (ADA, XL-SCID), IVID, avoidance live viral vaccines, irradiation blood products, prophylactic antibiotics
Defects of phagocytic cell treatment
Prophylactic abx, avoidance of live viral vaccines in some patients, gamam interferon in CGD, bone marrow transplant in some
Complement immunodeficiency treatment
symptomatic care, frequent use of abx, immunizations with bacterial polysaccharide vaccines
Primary immunodeficiency
Caused by genetic abnormality that can occur at any phase of the immune response
