Immunodeficiencies Flashcards
1
Q
SCID Genetic Defects (3)
A
- X-SCID - X-linked; mutation in common gamma chain in receptors of many cytokines —> T cells cannot proliferate in response to IL-7 during maturation —> less mature T cells in body so dec in cell-mediated response and humoral (b/c need helper T cells to activate B cells); also NK cell deficiency b/c cannot respond to IL-15 (proliferation and activation)
- ADA and PNP deficiencies - adenosine deaminase OR purine nucleotide phosphorylase - deficiency —> toxic purine metabolite buildup in cells that make DNA a lot AKA cells that proliferate so T cells affected during maturation; B cells mainly affected b/c no helper T cells
- Can also be Jak3 mutation (kinase in common gamma chain pathway of cytokines) OR RAG1/RAG2 mutations (problems w/ recombination)
2
Q
5 SCID Categories and Diagnosis
A
- Diagnostic Criteria
- Negative for HIV
- Absent/low # T cells and no/low T cell function OR presence of T cells of maternal origin
- Categorization
- T-B+NK- …common gamma chain problem; B cells present but not functioning normally
- T-B+NK+ …TCR specific problem
- T-B-NK+ … problem w/ RAG1/RAG2or artemis so no recombination (B and T cells affected)
- T-B-NK- …ADA or PNP problem w/ DNA synthesis and repair so affects all cells that proliferate
- Atypical SCID/Omenn Syndrome …partial defect—> SCID phenotype w/ red and scaly skin, high IgE, oligoclonal T cells present (may appear normal WBC count)
3
Q
SCID Screening
A
Screening - Newborn Screen - use T cell receptor excision circles (TRECs) in dried blood which tells # naive T cells leaving thymus
4
Q
X-linked Agammaglobulinemia
A
- only BCells
- Mutation in Bruton tyrosine kinase —> pre B cells fail to expand, proliferate, mature —> absence or marked dec in mature B cells and Ig in serum and low BTK protein in serum
- Usually present around age 2 w/ otitis, pneumonia, sinusitis, etc AND small/absent lymph nodes, tonsils or adenoids
5
Q
DiGeorge Syndrome
A
-Only T cells
- Incomplete development of thymus —> no T cell maturation; improves w/ age b/c some thymus tissue grows
- Most patients have partial DGS so some thymus
- Susceptible to opportunistic infections
- Treat w/ thymus transplant and Ca++ supplementation and abx
6
Q
Bare Lymphocyte Syndrome
A
- I- lack of MHC I b/c mutation in TAP1 TAP2 or tapasin genes —> CD8+ cells do not mature; viral infections but NOT opportunistic infections
- II- failure to express class II MHC b/c mutation in transcription factors —> CD4+ cells do not mature —> low Ig levels and lack of proper response to vaccines; opportunistic infections BUT proliferate normally in response to PHA
7
Q
X-linked Hyper-IgM Syndrome
A
- mutation in X-linked gene for CD40L —> defective T-cell dependent B cell responses (affinity maturation and isotype switching) AND defective T-cell dependent macrophage activation
- Rare subset have defect in AID (isotype switching)
8
Q
Common Variable Immunodeficiency (CVID)
A
- group of disorders characterized by poor antibody response to infections; reduced serum levels of IgA, IgG and IgM due to a number of underlying mutations in genes for B cell maturation and activation —> recurrent infections, autoimmune disease and lymphomas plus risk of cancer
- Usually present later; teens or 20s
- Notice that they do not properly make titers in response to vaccines
- Can have a VARIETY of phenotypes/presentations
9
Q
Transient Hypogammaglobulinemia of Infancy
A
- transplacental IgG gone by 6 mo; infant might not make own IgG at first but usually corrects by 24 mo
10
Q
Which Antibody Deficiency is Most Common?
A
- IgA deficiency is common (1 in 700) but no major symptoms in 2/3 of people; may have recurrent infections, allergy, autoimmunity
- Characteristic b/c NO IgA instead of just low amounts
11
Q
Chronic Granulomatous Disease
A
- mutation in gene encoding phagocytes oxidase (most commonly X-linked CYBB gene encoding gp91phox) —> neutrophils and macrophages cannot kill ingested microbes—> compensate by recruiting more macrophages and activating T cells —> collection of phagocytes that resemble a granuloma
- Recurrent and severe infections to:
- Staph aureus
- Serratia
- Burkholderia
- Nocardia
- Candida
- Aspergillus
- Diagnose via DHR assay (DHR ingested by phag - normally turn fluorescent if NADPH oxidase oxidizes it; if not work no fluorescence)
- Recurrent and severe infections to:
12
Q
Leukocyte Adhesion Deficiency (2 Types)
A
- mutations in genes encoding trafficking molecules
- LAD 1 - mutation in ITGB2 which encodes CD18 —> lack of adhesion of leukocyte to endothelial wall
- LAD 2- more rare; mutation in GDP-fucose transporter —> lack of fucosylation —> lack of E-selectin ligand —> impaired rolling
- Clinical presentation = high WBC (stuck in serum), impaired wound healing, periodontitis, absence of pus, leukocytosis, infected umbilical cord (omphalitis)
- **Also mental and physical retardation in LAD 2; may supplement w/ fucose
13
Q
Wiskott-Aldrich
A
- X-linked defect in WASP gene which regulates actin cytoskeleton of T cells and platelets —> problems w/ TCR signaling and T-B cell interactions and platelet formation
- Present w/ petechiae and small platelet size, eczema and recurrent infections
14
Q
Ataxia-Telangiectasia
A
auto recessive defect in ATM gene (regulates DNA dbl strand break repair)
- Present w/ red sclera, staggering (cerebellar ataxia), radiation sensitivity, dysgammaglobulinemia, lymphopenia, malignancy, low IgA, low molecular weight IgM, inc infections and elevated alpha fetal protein
15
Q
6 Types of Acquired Immundeficiency
A
- HIV - depletion of CD4+ cells
- Irradiation and chemo- dec bone marrow precursors for all leukocytes
- Immunosuppression therapy for graft rejection or inflammatory disease
- Involvement of bone marrow by cancers - reduced maturation
- Protein/calorie malnutrition- metabolic derangement —> inhibit lymphocyte maturation and function
- Removal of spleen - dec phagocytosis
16
Q
HIV Virus
A
- Retrovirus that affects mainly CD4+ T cells —> progressive destruction
- Viral particle = 2 identical RNA strands encapsulated in cone-shaped p24 capsid protein; lipid bilayer membrane w/ viral glycoproteins (transmembrane gp41 and external gp120 subunits)
- Viral RNA encodes structural proteins, various enzymes, and proteins that regulate transcription of viral genes and the viral life cycle
17
Q
6 Steps of HIV Infection
A
- 1- HIV virion binds CD4+, macrophage or dendritic cell @ p120 —> conformation change —> allows it to further bind to chemokine receptor on host plasma membrane
- R5 viruses use CCR5 receptor and infect T cells, macrophages, dendritic
- X4 viruses use CXCR4 receptor and infect ONLY CD4+ cells
- 2- Viral and host membranes fuse —> viral genome now in cytoplasm
- 3- Reverse transcriptase-mediated synthesis of proviral DNA
- 4- Proviral DNA integrated into cell genome via integrase
- 5- transcription/translation —> synthesis of HIV proteins that are cleaved by protease then assembled into new viral particles
- 6- Expression of gp120/gp41 on cell surface; budding of mature virion
18
Q
How does HIV prevent its own eradication?
A
- Virus rapidly mutates the portion of the gp120 glycoprotein recognized by antibody (cannot be neutralized)
- Virus prevents expression of class I MHC by host cell (down-regulate MHC I)
- When antibody-coated viral particles are phagocytosed by binding Fc receptors this just gains them entry for replication in these cells
- If CTLs kill any infected cells they are cleared by macrophages - spread infection
19
Q
Clinical Features of HIV/AIDS
A
- Acute HIV Syndrome - fever and malaise early after initial infection; only lasts few days
- Latency - few symptoms but progressive decline in CD4+ count in blood (considered AIDS once below 200 cells per mm3); also destruction of lymph tissue architecture
- Clinical AIDS- inc susceptibility to infections and some cancers
- Opportunistic infections by intracellular viruses (ex - cytomegalovirus)
- Oncogenic viruses (ex- B cell lymphoma from Epstein Barr Virus or Kapok’s sarcoma in blood vessels from herpesvirus)
- Bacterial infections b/c B cell antibody response depends on T helper cells
- Wasting/cachexia - loss of body mass b/c changes in metabolism and not eating as much; inc in TNF-alpha
- Dementia - if infection of macrophages in CNS (microglial cells)
20
Q
HIV Therapy
A
- HAART- highly active anti-retroviral therapy or ART - anti-retroviral therapy; block activity of reverse transcriptase, protease and integrase enzymes
- Result = now opportunistic infections and cancers less common (RARE)
- BUT still experience Chronic HIV-Associated Inflammation and Immune Activation (constant inflammation and immune activation —> greater incidence of malignancies, metabolic disorders and cardiac problems)
- Trying to develop vaccine
21
Q
Phases of Progression from HIV –> AIDS
A
- Virus infects CD4+ cells, dendritic cells and macrophages in blood or at epithelium (primary infection) especially mucosal CCr5+CD4+ effector memory T cells
- Then brought to lymph tissue and infects T cells there
- Massive viral replication, depletion of CD4+ and follicular hyperplasia
- Acute immune response (acute phase reactants, cytokine burst, anti-HIV antibodies and HIV-specific CTLs released)
- But still chronic infection in lymph tissue - virus trapped in lymph; low level viral replication; dec in lymph node architecture; T cell exhaustion (dec proliferation, dec cytolytic activity and inhibitory receptors present) clinical latency
- THEN HIV infection or other microbe infection —> cytokines —> inc viral replication —>destruction of lymphoid tissue and depletion of Cd4+ cells —> AIDS
- Death of both infected T cells during viral replication and death of UNINFECTED T cells (likely due to apoptosis stimulated by certain cytokines)
