Immunodeficiency Flashcards
congenital or primary immunodeficiency
immunodeficiencies due to genetic defects in one or more components of the immune response that result in increased susceptibility to infections
acquired or secondary immunodeficiency
non-genetic, develops in response to exogenous trauma or factors, e.g., malnutrition, treatment with immunosuppressive drugs (chemotherapy, prevention of transplant rejection, autoimmunity), bone marrow-derived cancers, infection (e.g., HIV)
what are some of the Immune System Abnormalities in Immunodeficiencies?
- Components of innate immune response
- Various stages of lymphocyte development/
maturation - Specific responses of mature lymphocytes
Three main categories of Congenital Immunodeficiency Diseases
- B cell deficiency
- T cell deficiency
- innate immune response
mechanism behind chronic granulomatous disease
- defect in production of reactive oxygen intermediates by phagocytes
- can be due to mutations in genes encoding components of the phagocyte oxidase enzyme
mechanism behind leukocyte adhesion deficiency-1
- absent or deficiency in expression of B2 integrins causing defective leukocyte adhesion-dependent functions
- can’t bind to endothelium or T cells to APC
mechanism behind leukocyte adhesion deficiency-2
- absent or deficient expression of leukocyte ligands for endothelial E- and P-selectins, causing failure of leukocyte migration into tissues
- binds to endothelium weakly
- lack of good migration into site of infection
mechanism behind Chediak-Higashi syndrome
- defective lysosomal function in neutrophils, macrophages, and dendritic cells, and defective granule function in natural killer cells
- not able to kill microorganism
- mutation in gene encoding a lysosomal trafficking regulatory protein
Describe some of the Mutations in critical components of early lymphocyte development/ maturation pathways that result in defects in B and T cell maturation
…
molecules required for the development of common lymphoid precursor cells into Pro-B and Pro-T cells
γc= common γ chain
JAK3 = (signaling molecule)
ADA
PNP
*defect in any of these creates problems for development of B and T cells
molecules required for the development of Pro-B and T cells into Pre-B and T cells
Molecules associated with VDJ recombination (for antibody production or TCR function)
RAG1
RAG2
ARTEMIS
*defect in any of these creates problems for development of B and T cells
molecules required for the development of Pre-T cell into immature CD4 CD8 T cells
Pre-TCR checkpoint: CD3
molecules required for the development of mature CD8 and CD4 T cells
CD8+ = ZAP70, TAP1, 2
CD4+ = MHC Class II
molecules required for the development of mature B cells
Pre-BCR checkpoint for BTK
defects in innate immunity that can cause immunodeficiencies
- cannot express B2 integrins: can’t bind to endothelium or T cells to APC
- defect in E or P selectins: needed for trafficking of cells to infection
- deficiency in complement cascade
Severe Combined Immunodeficiencies (SCID)
Affects both humoral and cell-mediated immunity:
- Defects in cytokine signaling
- Defects in nucleotide salvage pathways
- Defects in V(D) J recombination
- Defective thymic development
mechanisms behind some of the forms of SCID
- Decreased T cells with normal or increased B cells but with reduced Ig ability: defect in common gamma chain; defective T cell maturation due to lack of IL-7
- Progressive decrease in T and B cells (mostly T): cells are poisoned because of ADA or PNP deficiency leading to accumulation of toxic metabolites in lymphocytes
- decreased T and B cells; reduced serum Ig: defective maturation of T and B cells; may be mutations in RAG genes and other genes involved in VDJ recombination
oral symptoms of SCID
Candidiasis, viral infections, ulcerative stomatitis
Antibody Deficiencies
- Agammaglobulinemias *Hypogammaglobulinemias/isotype defects *Hyper-IgM syndromes
*defects in B cell maturation
Decrease in all serum Ig isotypes and reduced B cell numbers is a defect in…
Pre-B receptor checkpoint defect; Btk mutation (Bruton tyrosine kinase); mutations in IgM (can’t isotype switch)
Selective IgA deficiency
Decreased IgA and association with increased susceptibility to bacterial infections and protozoa
common variable immunodeficiency
- decreased IgG (hypogammaglobulinemias)
- normal or decreased B cell numbers
What would a mutation in CD40L (x-chromosome) or CD40 result in?
Defects in T helper cell-mediated B cell, macrophage, and dendritic cell activation; defects in somatic mutation, class switching, and germinal center formation; defective cell-mediated immunity
Defects in T cells
- Defects in MHC expression
- Defective T cell signaling/activation
- Defective thymic development
Bare lymphocyte syndrome
defective MHC class II expression and deficiency in CD4+ cells; defective cell-mediated immunity and T-cell dependent humoral immune responses
MHC Class I
- mutations in TAP1 or TAP2 (responsible for shuttling antigens into APC mechanism)
- results in decreased MHC Class I levels; reduced CD8+ T cells
Wiskott-Aldrich syndrome
- Defective T cell activation and leukocyte mobility
- mechanism based on TCR-dependent actin-cytoskeletal rearrangements are defective because of mutations in WAS, an X-linked gene mutation in WIP
DiGeorge Syndrome
- decreased T cells; normal B cells; normal or reduced Ig
- mutations in gene required for thymus development
Distribution of primary immunodeficiencies
- B cell defect make up 65%: this is because patient most likely to still survive
- SCID makes up 15%: surprising
- IgA deficiency by far most common
statistics on HIV
- ~37.9 million people living with HIV worldwide
- ~1.7 million people become infected per year; ~75 million people have been infected with HIV total
- 770,000 die per year, down from a high of 1.7 million per year in 2004; ~32 million have died total
- 70% in Africa and 20% in Asia
HIV transmitted through…
exchange of body fluids (e.g.,
blood, semen, etc):
- Sexual contact
- Mother-to-child transmission
- Infected blood or blood products
HIV virus family
Lentivirus family of retrovirus: RNA genetic material - 2 strands reverse transcribed into double-
stranded DNA incorporates into host genome (provirus)
HIV glycoproteins required for infection
gp120 and gp 41
HIV enzymes required for viral replication
Reverse transcriptase, integrase, and viral protease
Receptors required for HIV infection
CD4 and chemokine receptors, CXCR4 (T cells) and CCR5 (macrophages) required for infection; some HIV strains are macrophage-tropic, some are T cell-tropic (more virulent)
HIV primarily infects what cells?
CD4 T cells, macrophages and dendritic cells
HIV ___ Provirus can remain inactive for months-years, and activation (e.g., antigen, cytokines) of infected cells induces viral production
provirus
HIV infection of cells occurs…
Infection of cells occurs directly by free viral particles or through fusion of infected and non-infected cells.
HIV life cycle
- viral particles floating in serum binds to CD4 surface and chemokine receptor
- integrates into membrane and fuses with membrane
- viral material enters the cell
- in the cell, RNA in reverse transcribed from RNA into DNA
- upon activation, transcription of HIV genome occurs
- viral RNAs make proteases and other enzymes create the HIV core structure which gets incorporated into membrane
*provirus can reman latent for many years
progression of HIV infection
- infection of mucosal tissue
2 death of mucosal memory CD4 cells - DC or draining of lymphatics takes It to lymph nodes where infection is then established
- spread of infection throughout whole body: viremia
- immune response: some antibodies formed and CTL induced: partial control of virus infection
- over time, establishment of chronic infection: clinical latency. More infections occur.
- AIDS: destruction of lymphoid tissue: depletion of CD4+ T cells
clinical course of HIV
- acute response within first few weeks
- clinical latency over years
- 200 or below CD4+ cells is AIDS: opportunistic infections develop from here
Mechanisms of Immunodeficiency caused by HIV
- Direct toxic effects of infection on CD4 T cells
- Chronic activation of CD4 cells results in apoptosis
- Infected CD4 cells can be killed by CTL or ADCC
- Possible viral-mediated interference with CD4 function
- Macrophages are not killed by HIV and may act as viral reservoir (virus enters through CCR5); may have impaired APC function and cytokine secretion
- Dendritic cells are not killed by HIV and likely infect CD4 cells directly.
- Follicular dendritic cells may act as viral reservoir and/or may be impaired and/or destroyed by virus
What are the Direct toxic effects of HIV infection on CD4 T cells?
- Viral production compromises plasma membrane, leading to lethal influx of Ca++ or osmotic lysis
- Viral production compromises cellular protein synthesis
- Non-cytopathic HIV infection activates inflammasome pathway, and induces cell death; can lead to recruitment of cells that then become infected.
- HIV-induced fusion between cells results in cell death
What is the Immune Response to HIV?
- CD8 cells expand but provide only limited protection (primarily during acute phase); may be initially effective but result in virus that has lost specific CTL epitopes
- CD4 cells help CD8 cells, and may also be directly cytotoxic.
- Initial antibody response not neutralizing, later antibody response neutralizing (against gp120, critical for binding CD4) but cannot keep up with production of virus; only a small percentage of individuals develop high affinity neutralizing antibody to the critical CD4 binding site of gp140.
- Elimination of CD4 cells severely limits immune response capacity over time
- HIV has effective immune evasion strategies
Mechanisms of Immune Evasion by HIV
- HIV has extremely high mutation rate (error-prone reverse transcription) and can, therefore, evade immune response (most effective)
- Viral epitopes may be shielded by N-linked sugars
- HIV may downregulate Class I expression (less likely to be CD8 target)
- Induce immune deviation: HIV may induce Th2 cytokine- producing cells that inhibit cell-mediated (Th1-mediated) activity
- Impairs dendritic cell activity
- May also induce/activate regulatory T cells
- The latter two could also contribute to the compromised response to other microbes
clinical features of acute HIV disease
fever, headaches, sore throat with pharyngitis, generalized lymphadenopathy, rashes
clinical features of Clinical latency period of HIV
Declining blood CD4+ T cell count
clinical features of AIDS
opportunistic infections: protozoa, bacteria, fungi, viruses, tumors
Untreated oral manifestations in AIDS patients
- Oral hairy leukoplakia (Epstein-Barr Virus, EBV)
- Kaposi’s sarcoma(Human Herpesvirus 8, HHV-8)
- Necrotizing periodontitis
- Candidiasis (fungus)
Treated AIDS patients oral manifestations
- Human papillomavirus (HPV)
- Caries
what treatment mechanisms are helpful in HIV/AIDS?
- reverse transcriptase inhibitors
- protease inhibitors
- Fusion or Entry inhibitors
- integrase inhibitors
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
nucleoside analogues that inhibit reverse transcriptase activity - several different types now available and used in combination (e.g., AZT)
Non-Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRTIs)
bind directly to reverse transcriptase and inhibit its activity - several different types now available and used in combination
Protease inhibitors
inhibit proteases that are required for protein processing into viral capsid and core proteins, and therefore, HIV replication
Fusion or Entry inhibitors
prevent virus from binding or entering cells (target CD4 or CCR5 on cells or gp41 or gp120 on virus)
Integrase inhibitors
interferes with integrase which is needed for HIV to insert its genetic material into cells
what makes vaccines for HIV/AIDS very difficult?
ability of HIV to mutate; must elicit both cell-mediated and humoral response; other new approaches include gene therapy where antibody against HIV or a CD4/CCR5 fusion protein that blocks viral entry is expressed via viral vectors in individuals
