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
Selective T cell deficiencies:
Wiskott-Aldrich syndrome (can’t move receptors around because of cytokeleton dysfuction, lack of activation)
DiGeorge Syndrome
Defective T cell activation
TH1 (atypical mycobacterial infections) and TH17 defiencies (chronic yeast and staph infections)
Both B and T cell defects (SCID)
Ataxia-Telangiectasia (no VDL recombination)
Complement Protein defecits lead to susceptibility to
bacterial infections, AI, defective immune complex clearance
Secondary Immunodeficiencies
HIV infections, cancer tx, nutritional
Patient with normal B cell, CD4, CD8 counts despite hx of severe infections response to anti-CD3 stimulation low. Dx?
Wiskott Aldrich Syndrome: you can rearrange your cytoskeleton upon stimulation
3 cousins all dies of mycobcterium infections. Mutated allele in which gene?
IFNgamma stimulates macrophages to destroy intracellular mycobacterium
radiosensitive assay shows low lymphocytes surviving radiation. Which deficiency would patient have?
Lack ATM
What infection would pt. be susceptible to wits asplenia/splenectomy hx?
Pneumococcus-specific IgG2
What are the common features of XLA, Hyper-IgM, and Asplenia?
- Infections begin during transient hypogammaglobulinemia
- EC pathogens (typically sinusitis, bronchitis, otitis, pneumonia
What would lab values show for XLA?
Pre B cell receptor signaling is defective so
No B cells
What would lab values show for Hyper-IgM
B cell development is normal but class switching off
NML/IgM normal or increased if infection
decreased IgG/IgA
normal B cells.
What would lab values show for asplenia?
US for presence of a spleen
Howell-Jolly bodies which represent failure to clear RBCs
CVID lab values?
low IgG and low IgM and/or IgA
