Immunology Diseases Flashcards
DiGeorge Syndrome
Cause:
Chromosomosal deletions of 22q11.2
General Description: conotruncal defect due to abnormal development of 3rd and 4th pharyngeal pouches of the neural crest leading to midline defects including aplasia/hypoplasia of the thymus
- ->Cardiac issues: interrupted aortic arch, tetralogy of Fallot, ventral septal defects
- ->Parathyroid: hypocalcemia
- *–> Immune system: l_ow/absent T cells_, autoimmune disease; **Majority of patients have partial DGS with deficits in T cell numbers and low/normal mitogen responses, and can have normal to low antibody levels and responses to pneumococcal polysaccharide antigen
Severely affected patients susceptible to opportunistic infections such as Pneumocystis jiroveci, as well as frequent viral infections
–>Facial features: dysmorphic (low set ears, telecanthus w/ short palpebral fissues, short philtrum)
Treatment: thymis transplant, calcium supplementation, prophylactic antibodies
Severe Combined Immunodeficiency General
Symptoms include: failure to thrive, candidiasis, chronic diarrhea, opportunitistic infections, (some) significant dermatitis/ecezema
Marked T cell dysfunction, T cell lymphopenia as well as lack of B cell number and/or function
small and dysplastic thymus in almost all forms
Phenotype depends on genetic defect; defects can be in lymphocyte survival, in gene rearrangement and in cytokine mediated signaling
Forms of SCID are categorized based on lymphocytes
Forms of SCID
- T-B+NK-
a. gc (common gamma chain), JAK3, CD45, Lck, IL-2Ralpha
b. Half of SCID is Xlinked and due to gc chain defect
c. T cells absent, B cells present in normal numbers but not functional
d. These are involved in cytokine signaling
e. 50% of SCID is Xlinked and due to γc chain defect - T-B+NK+
a. IL-7Rα, CD3γ, CD3δ, CD3ε, CD3ζ
i. These are TCR specific or impt in Tcell proliferation - T-B-NK+
a. RAG1, RAG2, artemis, Cernunnos
i. These are involved in T and B cell gene rearrangement - T-B-NK-=ADA (adenosine deamninase deficiency)
a. ADA, Reticular dysgenesis, PNP
i. Metabolism or production issues not specific to lymphocytes
b. 15-20% from ADA deficiency
c. Defect in purine salvage pathway leading to lymphocytotoxic accumulation of adenosine and deoxyadenosine and metabolites, which inhibit DNA synthesis and repair
d. Half of patients have skeletal findings, hearing loss, behavioral issues
Omenn syndrome
I. partial defect in RAG1/2, ARTEMIS, IL-7R defect
II. SCID phenotype with erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, high IgE
III. Oligoclonal T cells present–>can give a normal WBC count
SCID Treatment
TREATMENT
Must avoid live vaccines, and all blood products must be irradiated to prevent graft vs host disease
May be possible to replace ADA in ADA SCID patients until they can be transplanted
>95% survival if BMT within the first 3 months of life drops to 50% survival after 1 year of age
SCID SCREENING
SCID is being added to the newborn screen and is done by looking for TRECS (T cell receptor excision circles) in dried blood spots on guthrie cards by rtPCR
TRECS are episomal nonreplicative DNA circles that are excised during T cell receptor rearrangement
indicates number of naïve T cells leaving the thymus
Bare Lymphocyte Syndrome I
lack of MHCI expression due to mutations in TAP1, TAP2 or tapasin genes (lack of intrathymic maturation of CD8 Tcells)
Pts have difficulty fighting viral infections (esp. respiratory–>chronic uppper respiratoy infection)
Pts do not have opportunistic infections
Bare Lymphocyte Syndrome II
Rare autosomal recessive disease
Presents phenotypically like SCID w/ susceptibility to opportunistic infections but unlike SCID, cells have a normal mitogen response to PHA
Defect in transcription factors that regulate expression of MHCII leads to lack of MHCII expression–>defecetive maturation of CD4 T cells–>low Ig levels and lack of proper response to vaccinations
Wiskott-Aldrich Syndrome
X linked defect in WASP gene
WASP gene regulates actin cytoskeleton of T cells and megakaryocytes
Defect leads to problems with T cell receptor signalling and T: B cell interactions and platelet formation
Symptoms: petechiae, thrombocytopenia, eczema, infection (can lead to opportunistic infections)
Ataxia-Telangiectasia
AR disease due to defect in ATM gene, a key regulator of cellular response to DNA double strand breaks
Progresssive cerebellar ataxia-early
Oculocutaneous telangiectasia-late
Radiation sensitivity
Dysgammaglobulinemia, lymphopenia
low IgA, LMW IgM, increased sinopulmonary infections
Malignancy
Elevated serum AFP in 95% of pts
X-Linked Agammaglobulinemia
A. Block in B cell maturation
B. Defect is in BTK (Bruton’s tyrosine kinase)
C. Usually well during first few months of life (mother’s IgG), than sick with otitis, sinusitis, pneumonia, diarrhea
D. Small or absent lymph nodes, tonsils and adenoids
E. Low or absent B cells
F. Treatment is IVIG and sometimes daily prophylactic antibiotics
Hyper IgM Syndrome 1
CD 40 Ligand deficiency:
- CD40L interacts with CD40 on B cells, interaction causes B cell to proliferate and isotype switch
-Have a normal number of B cells but they can’t isotype switch
-High or normal IgM with low A, G and E
-Bacterial and opportunistic infections
-Liver disease and cryptosporidium infection
-Increased incidence of autoimmunity and cancer
-Tx is a bone marrow transplant
X linked
Hyper IgM Syndrome 3
CD 40 Deficiency
- Autosomal recessive
- Should interact with CD40 ligand on T cells
- Susceptible to bacterial and opportunistic infections
- B cells can not class switch
- Tx is IVIG and prophylactic antibiotics
Hyper IgE Syndrome
A. AD-HIES (Job’s Syndrome)
a. Elevated IgE with decreased specific antibody production
b. STAT 3 mutation
c. Facial features, bone fractures, delayed shedding of primary teeth, hyperextensible joints, bacterial infections
B. AR-HIES
a. Mutation in DOCK 8 associated with reduced B and T cells
- cutaneous viral and staph infections
- cancer, atopy and anaphylaxis
b. Mutation in TYK2
- normal T and B cells
- susceptibility to mycobacteria and salmonella
Common Variable Immunodeficiency
A. Reduced levels of one or more immunoglobulin and impaired antibody production.
B. Recurrent respiratory tract infections
C. More prone to autoimmune disease and lymphomas
D. TACI/ICOS mutations
E. Treatment is IVIG
F. Risk for cancer and bronchiectasis
defect in B cell differentiation
Selective IgA Deficiency
A. Most common primary immunodeficiency (1:700)
B. 2/3 people with disease are asymptomatic
C. Recurrent infections, autoimmunity, allergy
D. Reason why B cells fail to switch to produce IgA is unknown
E. Treatment is prophylactic antibiotics
F. Monitor for development of CVID
