Immunodeficiency diseases

Which are collectively called immunodeficiency diseases. Definition: Defects in one or more components of the immune system lead to serious and often fatal disorders. Which are collectively called immunodeficiency diseases.

Two major types of immunodeficiency diseases Secondary immunodeficiencies immunodeficiency resulting from infections and other diseases immunodeficiency resulting from iatrogenic causes immunodeficiency due to aging or malnutrition Primary immunodeficiency Inherited immunodeficiencies

General Features: The principal consequence of immunodeficiency is an increased susceptibility to infection. Patients with immunodeficiencies are also susceptible to certain types of cancer. Immunodeficiency may result from defects in lymphocyte maturation or activation or from the effector mechanisms of innate and adaptive immunity.

Secondary immunodeficiencies Immunodecifiency caused by infectious agents Many bacterial, viral and parasitic agents compromise the host immune functions, most prominent among them is HIV infection Immunodeficiency resulting from aging and malnutrition A number of immune functions become less efficient with aging Immunodeficiency during malignancy and other diseases, immunosuppressive drugs

Immunologic defects caused by HIV infection

HIV Structure Life cycle See the three videos

CD4+ T cell numbers during HIV infection

CD8+ T cell numbers during HIV infection

NK cell function among AIDS patients (% cytotoxicity)

The cellular and immunological picture - The course of the disease HIV and AIDS The cellular and immunological picture - The course of the disease

The cellular and immunological picture The course of the disease HIV and AIDS The cellular and immunological picture The course of the disease 1. Acute Infection High virus titer (up to 10 million viruses per ml blood) Mild symptoms Fall in CD4+ cells but recovers Rise in CD8+ cells but recovers Macrophages infected

HIV and AIDS 2. A strong immune response Virus almost disappears from circulation Good cytoxic T cell response Soluble antibodies appear later against both surface and internal proteins Most virus at this stage comes from recently activated and infected CD4+ cells (half life about a day) CD4+ cell production compensates for loss due to lysis of cells by virus production and destruction of infected cells by CTLs

HIV and AIDS Latency of virus and of symptoms 3. A latent state Latency of virus and of symptoms Virus persists in extravascular tissues Lymph node dendritic cells Resting CD4+ memory cells (last a very long time - a very stable population of cells) Resting CD4+ cells carry provirus

HIV and AIDS 4. The beginning of disease Massive loss of CD4+ cells CD4+ cells are the targets of the virus (direct cytopathic effects) Destruction by immune response (ADCC, CTL killing, unmaturation) Dendritic cells present antigen and virus to CD4 cells just as they are activated Epitope variation allows more and more HIV to escape from immune response just as response wanes Apoptosis of CD4+ cells HIV patients with high T4 cell counts do not develop AIDS

HIV and AIDS 5. Advanced disease - AIDS CD8+ cells destroy more CD4+ cells CD4 cell loss means virus and infected cells no longer controlled As CD4+ cells fall below 200 per cu mm virus titer rises rapidly and remaining immune response collapses CD8+ cell number collapses Opportunistic infections Death in ~2 years without intervention Good correlation between loss of CD4+ cells and onset of symptoms

Functional defects among AIDS patients Susceptibility to opportunistic infections Pneumocystis, toxoplasma, cryptococcus, herpes,CMV, Mycobacterium avium Neoplasms, cachexia kidney failure (HIV nephropathy), CNS degeneration (AIDS encephalopathy)

Treatment Highly Active Anti- Retroviral Therapy HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor Now also: Two nucleoside analog RT inhibitors and 1 non nucleoside See a video

Drug resistance

Vaccine Very difficult But still being in development

Developmental defect in primary immunodeficiencies ery pl neu m CD8+ CD4+ lym nk CTL antigen thy TH2 TH1 mye

Primary immunodeficiency diseases Stem cell defect Reticular dysgenesis

Primary immunodeficiency diseases T and B cell defect severe combined immunodeficiency X-linked IL2 receptor γ-chain (50%) Autosomal (20%) adenosine deaminase (ADA) purine nucleoside phosphorylase (PNP) RAG1 and RAG2 defects

    IL-4R IL-9R IL-15R IL-2R

Severe combined immunodeficiency Lack of Thymic shadow (x-ray) and T and B cells Lack of all Ig classes and subclasses No primary follicles and germinal centers Lymphoid hypo-cellularity of tonsil and Peyer’s patch Extreme susceptibility to bacterial, viral, parasitic infections Live vaccines are hazardous

Hypocelluarity of the thymus in SCID

Hypocelluarity of the lymph node in SCID

Hypocelluarity of the tonsil in SCID

Hypocelluarity of gut lymphoid tissue in SCID

Immunodeficiencies involving T cells Immunodeficiency of T cell DiGeorge syndrome T cell deficiency with some degree of B cell defect Wiskott-Aldrich syndrome Ataxia telangiectasia

DiGeorge syndrome Poor development or absence of thymus T cells absent or low in numbers A thymic graft can correct T cell defect Other defects due to aberrant fetal development Abnormal facial features Hypocalcemia due to defect in parathyroid Congenital heart defects

DiGeorge syndrome Low set, notched ears Fish mouth

Hypocelluarity of thymus DiGeorge

Hypocelluarity of lymph node in DiGeorge

T cell immunodeficiency due to MHC defects Deficiency resulting from MHC defect Class-II MHC defect (class-II trans-activator or a transcription factor defect) Class-I MHC defect (TAP protein defect)

MHC class II deficiency Bare lymphocyte syndrome Low or no expression HLA-DP, HLA-DR, HLA-DQ on B cells, macrophages and dendritic cells At least three genetic defects, CIITA, RFX-J and RFXAP T cells are near normal, CD4 cells decreased. Lymphocytes proliferate normally to PHA ,but poorly to antigen Immunoglobulin responses are poor

MHC class I deficiency Less common and less severe than MHC class II deficiency The defects is associated with the gene encoding TAP-1 or TAP-2 subunit of TAP complex Patients may have chronic aspiratory infection. A few patients gave both class I and class II MHC deficiencies

Ataxia telangiectasia Immune defects Reduced T cell-numbers and functions (PHA, con-A responses) Low IgG and IgA Non immune defects Lack of coordination Telangiectasis Defective DNA repair mechanism Break in TCR & Ig heavy chain genes

Wiskott-Aldrich syndrome Immune defects T cells normal in numbers; reduced functions Low IgM, normal IgG and elevated IgA and IgE Poor antibody response to polysaccharides Poor polyclonal T-cell response to lectins Non immune defects Eczema and petechia （瘀点） Thrombocytopenia and defective platelets Defective WASP (Xp11.22) Defective cytoskeletal organization

Immunodeficiencies involving B cells and or Ig X-linked (Bruton’s) hypo-γ-globulinemia Common variable hypo-γ-globulinemia Selective IgA deficiency Selective IgG deficiency Hyper-IgM deficiency (mutation of CD40L)

X-linked (Bruton’s) hypo- γ -globulinemia Low B cell numbers Low immunoglobulin classes and subclasses Defect in btk (Bruton’s tyrosine kinase) gene

Common variable hypogammaglobulinemia Acquired in the 2nd or 3rd decade of life All immunoglubulins decline Cause unknown

Immunodeficiency of the non specific immune system Phagocyte defects Cyclic neutropenia Chronic granulomatous disease Leukocyte adhesion defect Chediak-Higashi syndrome Complement deficiencies

Phagocyte defects (1) Cyclic neutropenia Poor regulation of neutrophils Chronic granulomatous disease Defect in NADPH oxidase (cytochrome-b558) Poor NBT (nitroblue tetrazolium test) reduction

Phagocyte defects (2) Leukocyte adhesion defect Defect in CD11a (LFA-1) or CD11b (mac-1) Chediak-Higashi syndrome Poor phago-lysosome fusion Poor NK cell activity

Poor intracellular killing and NBT-reduction tests in CGD

Complement deficiencies C3 deficiency Due to poor C3 synthesis Due to a deficiency of factor I or H C1-C9 deficiency Poor synthesis of individual components C1-INH deficiency Hereditary angioedema

C1-inhibitor deficiency: angioedema

Indicate whether each of the following statements is true or false. If you think a statement is false, explain why. a. DiGeorge syndrome is a congenital birth defect resulting in absence of the thymus. b. X-linked agammaglobulinemia (XLA) is a combined B-cell and T-cell immunodeficiency disease. c. The hallmark of a phagocytic deficiency is increased susceptibility to viral infections. d. In chronic granulomatous disease, the underlying defect is in a cytochrome or an associated protein.

e. Injections of immunoglobulins are given to treat individuals with X-linked agammaglobulinemia. f. Multiple defects have been identified in human SCID. g. Mice with the SCID defect lack functional B and T lymphocytes. h. Mice with SCID-like phenotype can be produced by knockout of RAG genes. i. Children born with SCID often manifest increased infections by encapsulated bacteria in the first months of life. j. Failure to express class II MHC molecules in bare-lymphocyte syndrome affects cell-mediated immunity only.