Immunodeficiencies Flashcards
Genetic causes of SCID (deficiencies in both B and T cells)
- X-linked
- Autosomal
- Blocks in lymphocyte maturation
- About half are X-linked: only males affected
- For X-linked: 99% due to gamma chain signaling subunit mutations leading to absence of T cells (IL-7) and NK cells (IL-15)
- Autosomal SCID: mutations involved in purine salvage pathway: ADENOSINE DEAMINASE (ADA) and PURINE NUCLEOSIDE PHOSPHORYLASE
- mutations in JAK3
- Omenn Syndrome (mutations in RAG1 or RAG2 leading to complete or reduced expression) rare
- Mutations in Kinasefor gamma chain signaling
Characteristics indicating immunodeficiency as underlying disease
- 8+ new ear infections in one year
- 2+ serious sinus infections within 1 yr
- 2+ Pneumonia’s w/in 1yr
- 2+ more months on antibiotics with little effect
- Failure of infant to gain weight or grow normally
- Recurrent deep skin or organ abscesses
- Persistent thrush in mouth or elsewhere on skin after age 1
- Need of IV Antibiotics to clear infections
- 2+ deep seated infections
- Family hx of primary immunodeficiency
basically: (8+ new ear infections, 2+: serious sinus infections, pneumonias, deep skin organ abscesses, deep deated infections; persistent thrush, no weight gain/growth, antibiotics don’t work and need IV antibiotics, family hx)
T cell deficiencies: presentation, nature of pathogen, age of onset
- REduced T cell zones
- LAB: REduced DTH reactions to common antigens
- LAB: Defective T cell proliferative responses to mitogens in nvitro
- Infections: Viral and microbial like Pneumocystitis jiroveci, atypical mycobacteria, fungi
- Virus-assoc malignancies (EBV-assoc lymphomas)
Basically:
Antibody deficiencies: presentation, nature of pathogen, age of onset
- Absent/reduced follicles and germinal centers
- LAB: Reduced Serum Ig levels
Cytokines that use common gamma chain
IL-2, 4, 7 (pro-T cells can’t mature when gamma subunit mutated), 9, 15 (NK cells deficient bc this IL receptor uses a gamma subunit as well), 21
basically: 2,4,7,9,15
Pro-T cells and NK Gamma chain cytokines and their common signaling pathways
IL-7 (VERY IMPORTANT) affects immature T-lymphocytes (esp. pro-T cells) inability to mature
IL-15 affects NK cell proliferation
DiGeorge Syndrome:
clinical features, the immunologic bases of the clinical presentation, the dx tests, tx
clinical features: heart defects, cleft palate, delayed development, INCOMPLETE DEVELOPMENT OF THE THYMUS due to anamalous devlpmnt of 3rd and 4th branchial pouches.
the immunologic bases of the clinical presentation: Deletions on 22q11.2, Low T cell numbers bc no thymus to mature in
dx tests: decreased T cells, normal B cells, normal or decreased serum Ig
tx: gets better with age as small amount of thymus develops.
BASICALLY: T cells can’t mature bc thymus deficient, low T cells in serum.
Bare Lymphocyte Syndrome I and II
clinical features, the immunologic bases of the clinical presentation, the dx tests, tx
immunological mechanism: Failure to express MHC II leading to impaired cell-mediated immunity and T-dependent antibody responses.
mutations: Transcription factors that induce MHC II; cell signal-transducing molecules, cytokines, various receptors
LAB: decreased CD4+ T cells because MHC II responsible for T cell maturation and activation
BASICALLY: MHCII not expressed, CD4+ t cells deficient and also T-dependent antibody responses impaired so often clinically characterized as SCID
Adenosine DeAminase Deficiency
clinical features, the immunologic bases of the clinical presentation, the dx tests, tx
clinical features: defective humoral immunity
immunologic mechanism: decreased ADA leads to buildup of toxic purine metabolites in proliferating cells. This injures lymphocytes which actively proliferate during maturation
Block in T cell maturation>Bcell maturation
mutation: adenosine Deaminase mutation
LAB: reduced serum Ig in ADA deficiency, normal B cells and serum Ig in PNP (purine nucleoside phosphorylase) deficiency
CVID (Common Variable Immunodeficiency)
clinical: poor antibody responses to infections, recurrent infections, Autoimmunity, lymphomas
LAB: reduced IgG, IgA, IgM
mutations/defects relatively unknown, mutations in B cell growth factors, costimulators.
Hyper IgM syndrome (types 1 and 2)
TYPE I: clinical features
the immunologic bases of the clinical presentation: Th cells don’t have CD154 (CD40L) to bind to B cell’s CD40 and induce class switching.
mutations: CD40L from T cells that bind to B cells and macrophages
the dx tests: IgM major serum antibody
TYPE II:
decreased activation induced cytidine deaminase leads to poor class-switching and poor somatic hypermutation
IFNgR1 deficiency
TH1 Deficiency
IL-12bR1 deficiency
TH1 Deficiency
IL-12 deficiency
TH1 Deficiency
Wiskott-Aldrich Syndome (Lymphocyte abnormality)
presentation: eczema, reduce blood platelets, immunodeficiency.
X linked
immunologic mechanism:
mutation: gene that encodes a protein that binds to various adapter molecules and cyotoskeletal components in hematopoetic cells. cause small platelets and leukocytes–>migration failure
X-Linked Agammaglobulinemia (b cell deficiency)
presentation: autoimmune diseases, idiopathic arthritis
mutation: X-linked Bruton Tyrosine Kinase (Btk) and defective/decreased enzyme prodn
immunomechanism: deficient/defective Btk stops B cells in the bone marrow from maturing past pre-b cell stage
LAB: decreased mature B lymphocytes and serum Ig levels
Basically: Btk mutation-> decreased Ig and B lymphocytes
Ataxia-telangeictasia
Lymphocyte abnormalities
presentation: gait abnormalities, vascular malformations, immunodeficiencies.
immunomechanism: defective lymphocyte maturation
mutations: DNA repair genes leading to abnormal repair
LAB: low lymphocyte numbers
Hyper IgM syndrome (types 1 and 2)
TYPE I: clinical features
the immunologic bases of the clinical presentation: defective CD40L on Th cells leading to defective B cell class switching
mutations: CD40L from T cells that bind to B cells and macrophages
the dx tests: IgM major serum
TYPE II: mutations in activation-induced deaminase (AID) leading to no Antibody class switching and no somatic hypermutation
Chediak-Higashi syndrome
clinical presentation: increased susceptibility to bacterial infections
Immunodeficiency: lysosomal granules of leukocytes do not fx normally. This affects NK cells.
rarely: TLR mutations, including NF-kappaB TF
mutations: gene encoding lysosomal trafficking regulatory proteinn
LAD-1 (leukocyte adhesion defect)
immunological mechanism: leukocyte fail to migrate to tissues due to absent/deficient expression of leukocyte ligands for endothelial E and P selectins; no rolling and binding
mutation: absence of CD18
Would antibody responses be normal in an X-linked SCID patient?
no because most Ab would be IgM in this patient
Which cell types are missing in a patient lacking RAG1 expression?
T cells and NK cells: need RAG to express the TCR
What is a common clinical manifestation of Omenn syndrome
Autoimmunity: few cells that escape might be selfreactive.
which might be a common symptom of IgA deficiency? and Best tx?
IBS because of mucosal immunity.
Tx: antibiotics
