Immunodeficiency Flashcards
Three broad scenarios in which people fail to mount an effective immune response.
- Congenital Immunodeficiency
- Pathogens incapacitate or evade immune system
- Host Conditions
Examples of ways pathogens may incapacitate of evade the immune system?
HIV, Multiple serotypes, mutations, gene conversion, hiding in dormant state, blocking immune response, auperantigens
Examples of host conditions that trigger immunodeficiency
Pregnancy Stress Malnutrition Cancer Aging
Three general signs of Immunodeficiency diseases
- Chronic Infections of Opportunistic Pathogens
- Inflammatory diseases due to persistent infection
- High incidence of cancer
You are immunodeficient if you have defects in….
TCR activation signalling molecules Immune cell TFs Mol/Organs of lymphocyte development Antigen presentation phagocyte function cytokines/co-stimulators Migration and Adhesion Complement DNA recombination/metabolism
Laboratory tests to assess T cell function?
Enumeration (Flow Cytometry) Functional Assays (Mitogen Resp., MLR, DTH Skin Tests)
Laboratory Tests to assess B cell function?
Enumeration
Circulating Ab levels
Lab tests to assess Macrophage function
Enumeration Functional Assays (Nitroblue tetrazolium)
Lab tests to assess complement
Direct measurement of complement components
Complement hemolysis assay
Three Primary B cell immunodeficiencies
X Linked Agammaglobulinemia (BTK Deficiency)
Common Variable Immunodeficiency (Acquired hypogammaglobulinemia)
Selective IgA dficiency (most common immunodefic.)
Three minor B cell immunodeficiencies
Transient hypogammaglobulinemia of Infancy
Selective deficiency of IgG subclasses
Immunodef. with hyper IgM
Primary T cell immunodeficiencies?
COngenital thymic aplasia (Digeorge’s or 3rd and 4th Phar Arch syndrome)
Two primary Combined B and T cell deficiencies (SCID)
X linked combined immunodef (defect of all cyto. receptors)
Adenosine Deaminase Deficiency
Less common causes of SCID?
Purine nucleoside phosphorylase def.
TCR immunodeficiency
MHC Class I or II Def.
Defective IL-2
Asplenia
Gene. Defect. Susceptibility.
Unknown
Absence of Spleen
Encapsulated extracellular Bacteria
C3 def.
Gene. Defect. Susceptibility.
C3
Lack of C3
Recurrent Infection with G- Bacteria
Factor I def.
Gene. Defect. Susceptibility.
CFI
Absence of Factor I, Depletion of C3
Encapsulated Bac
Look through the table in the powerpoint
I don’t care enough to type all of this out right now.
Immune defect in Paroxysmal nocturnal hemoglobulinuria
Lack of complement-regulatory proteins DAF, HRF, and CD59
Gene affected in chronic granulomatous disease?
NOX1 (NADPH Oxidase)
Genes potentially affected in Hyper-IgM deficiency
Activation induced cytidine deaminase
CD40
CD40L
IKBKG
Immune defect in Omenn Syndrome
Impaired VDJ Recombination
Immune defect in MHC Class I def.
Low MHC Class I Expression
Immune defect in X linked Agammaglobulinemia
B cells blocked at pro-B cell stage
Immune defect in Complete Digeorge Syndrome
Absence of Thymus/T cells
Immune defect in IPEX
Lack of Regulatory T cells and peripheral tolerance
MHC Class I and MHC Class II
Deficiency of which causes SCID?
Class II Def = SCID
Bubble Boy’s SCID was caused by…
Deficiency of Common gamma chain (CD132)
What is Common Gamma Chain?
Cytokine receptor subunit common to receptors for…
IL2, IL4, IL7, IL9, IL15, and IL-21 Receptor
What B cell immunodeficiency is most common?
What happens?
Selective IgA
Increased Respiratory Infections
X linked Agammaglobulinemia is caused by…
A defect in Bruton’s agammaglobulinemia tyrosine kinase (btk)
Causes Failure in B cell development
Three primary phagocyte deficiencies
Neutropenia
Chronic Granulomatous Disease
Leukocyte Adhesion Deficiency
Functional effect of Leukocyte Adhesion Deficiency
Defective Migration of Monocytes and Neutrophils to infected tissues.
Defective Uptake of opsonized pathogens
Functional effect of Chronic Granulomatous Disease
Defective respiratory burst
Phagocytes can’t kill pathogens
Primary complement deficiencies of Classic Pathway
C1, C4, C2, C3
Primary complement deficiencies of Alternative Pathway
Factor D, Properdin
Primary complement deficiencies of MAC
C5-9
Primary complement deficiencies of regulator proteins
Factors H, Factor I, C1 inhibitor hereditary angioedema
Problems seen in C1, C2, and C4 deficient?
Immune complex clearing
Problems seen in C3 deficiency
Major Immunodeficiency
Can’t opsonize
Problems seen in C5-C9 deficiency
Loss of Membrane Attack
Problems seen in Factor D, Properdin deficiency?
Can’t make and stabilize C3 convertase of the alt. pathway
How do we fix immunodeficiency?
Bone Marrow Transplant
Why is a high degree of HLA matching required to do a bone marrow transplant
- To prevent alloreactions (GvH disease) and rejection
2. For effective presentation of antigen to donor cells
Five categories of secondary immunodeficiencies
- Drug/Radiation Induced
- AIDS
- Nutritional Deficiency
- Autoimmune DIsease
- Other (Postviral, chronic infection, cancer)
Common drug induced immunodeficiency?
Steroids
Nutritional deficiencies associated with immunodef.?
Protein, Calorie, Biotin, B12, Iron, Vit A, Zinc
HIV. Mechanism of Immunodeficiency.
Depletion of CD4 Helper T cells
Protein-Calorie Malnutrition. Mechanism of Immunodeficiency.
Metabolic dearrangements inhibit lymphocyte maturation and function.
Irradiation and Chemotherapy treatments
Decreased bone marrow precursors for leukocytes
Cancer metastases to bone marrow
Reduced site of leukocyte development
Removal of spleen
Decreased phagocytosis of microbes
Describe the progression of AIDS (6 Steps)
Infection
Viremia
Immune Response to HIV
Temporary Reduction of Virus Infected CD4
Gradual decrease in CD4 Ts over 2-15 years
AIDS
Lab determinant of AIDS?
CD4 T cell count drops below 200
HIV enters through binding to what on the host?
CD4 and CCR5 or CXCR4
What state must a T cell be in to become infected with HIV
Activated
Needs NF-kB for RNA transcription
How do AIDS patients typically die?
Secondary Infection
What is an M trophic virus?
Infects macrophages, DCs, and some Ts through CCR5 (early stage virus)
What is a T trophic virus?
Infection T cells through CXCR4 (late stage virus)
Does the switch from M trophic to T trophic occur in all cases of HIV?
It occurs in approx. 50%
Two early proteins of HIV?
What do they do?
Tat and Rev
Increase transcription of viral RNA and RNA trans to cyto
Some populations have mutant ______ that lends resistance to HIV
CCR5
Progression of HIV infection is affected by what two genotypes
HLA-B
KIR3DL1/S1 (involved in NK activation)
Common opportunistic parasites
Toxoplasma
Cryptosporidium
Leishmania
Microsporidium
Common opportunistic bacteria
Mycobacterium
Salmonella
Common opportunistic fungi
Pneumocystis carinii
Cryptococcus neuformans
Candida
Common opportunistic viruses
Heres
CMV
VZV
Common opportunistic cancers?
Kaposi’s
Non-Hodgkin’s
Primary lymphomas of the brain
What makes HIV so bad?
High mutability and slow progression
Targets CD4
Single drugs are only transiently effective
How does HIV manage to evade host response by rapid mutation
Error prone reverse transcriptases allow variance
Selection for variants without epitopes for Immune syst.
Example of genetic variations within species preventing long term immunity
90 serotypes of strep pneumonia
How does influenza escape from immune response?
Mutation and recombination
Antigenic Shift –
Antigenic Drift –
Shift – Recombination/Swapping RNA, severe pandemics
Drift – Little genetic changes, mild/limited epidemics
How do tyypanosomes and gonorhea escape from immune response?
Gene conversion to change surface antigens
How does Herpes virus escape from immune response?
It hides in the dormant state in the nerves
Whats so great about hiding from the immune system in a neuron?
Neurons have low levels of MHC I
Two specific mechanisms for blocking antigen procesing and presentation?
Inhibition of MHC Class I upregulation of IFN-g
Inhibition of peptide transport by TAP
How does Vaccina inhibit humoral immunity?
Virally encoded complement control protein
Inhibits complement activation of infected cell
How does Vaccina inhibit inflammatory response?
Virally encoded soluble cytokine receptor
Blocks effects of cytokines by inhibiting their interaction with host receptors
How does herpes simplex and CMV block antigen processing/presentation?
Inhibition of MHC Class I expression
Causes impaired recog. by CD8 T cells
What does Herpes Simplex do to TAP to alter antigen processing and presentation?
Inhibition of Peptide Transport by TAP
Blocks Peptide Association with MHC I
How does Epstein-Barr virus immunosuppress the host
Virlaly encoded IL10 homolog
Inhibits Th1 lymphocytes, inhibits IFN-g
How does tuberculosis subvert the immune system
Prevents phagolysosome fusion
How does listeria subvert the immune system?
Escapes phagolysosome
How does Syphilis subvert the immune system?
Coats itself with human proteins
How does Stephylococci subvert the immune system?
Production of Superantigens
How does leprosy subvert the immune system?
Induces Th2 response to evade TH1 CMI response
Effect of superantigens?
Induce poly-clonal T cell activation, inhibiting antigen-specific immunity
High Cytokine Levels lead to patient going into Shock
How does SLP7 (stephylocccal superantigen like protein 7) work?
SSLP7 binds C5 and IgA, blocking the bacteria from opsinization
Problems of elderly immunodeficiency
Frequent Infections
Ineffective Vaccinations
Potential solutions for immunodeficiency in the elderly?
Almost none.
Administration of cytokines (IL2, 7, 10, leptin, GH, etc.)
New adjuvanted vaccine formulations for effective antigen presentation
In pregnancy, immunity is actively suppressed by secretion of….
alpha-fetoprotein
IL-10
TGF-beta
How do trophoblasts reduce their likelihood of immune rejection
Don’t express MHC I and II
What tends to happen to auto-immune diseases in pregnancy? Exception to the rule?
They tend to be suppressed, with a rebound postpartum
Systemic Lupus Erythematosus is exacerbated in pregnancy
What is hemolytic disease of the newborn?
How is it treated?
Anti-RhD (IgG) antibodies of the mother cross the placenta
Give mom anti-RhD antibodies during pregnancy/immediately post-delivery
Why doesn’t a Type O mother reject a Type A fetus?
IgM antibodies can’t get across the placenta
Two types of immunosuppressive drugs
Cycle-Nonspecific
Cycle-Specific
Examples of Cycle Non-specific immunosuppressive drugs?
Radiation, Corticosteroids, NSAIDS, cyclosporins
Examples of Cycle specific immunosuppresive drugs?
Cyclophosphamide
Chlorambucil
Azathioprine
Methotrexate
Two types of pathologically induced immunosuppression?
Immunodeficient Diseases
Disease-Induced Anergy
