Congenital and Acquired Immunodeficiencies

Question 0

What is the histopathology of B cell deficiencies?

Answer 0

Absent or reduced follicles and germinal centers in lymphoid organs. Reduced Ig serums.

Question 1

What is the cause of congenital immunodeficiencies?

Answer 1

Genetic defects that lead to blocks in the maturation or functions of different components of the immune system.

Question 2

What are the common infectious consequences of B cell deficiencies?

Answer 2

Pyogenic bacterial infections.

Question 3

What is the histopathology of T cell deficiencies?

Answer 3

Reduced T cell zones in lymphoid organs. Reduced DTH rxns to common antigens. Defective T cell proliferative responses to mitogens in vitro.

Question 4

What are the common infectious consequences of T cell deficiencies?

Answer 4

Viral and intracellular microbial infections (e.g. Pneumocystis carinii, atypical mycobacteria, fungi). Virus-associated malignancies (EBV assoc. lymphomas)

Question 5

What is severe combined immunodeficiency (SCID)?

Answer 5

A disorder with defects in both B and T cell arms of the adaptive immune system.

Question 6

What is the cause of 50% of cases of X-linked SCID and what is the consequence?

Answer 6

Mutations in a signaling subunit, gamma chain, of a receptor for cytokines (includes IL-2, IL-4, IL-7, IL-9, IL-15). When the gamma chains are non-functional, immature pro-T and pro-B cells cannot proliferate in response to mainly IL-7 ==> reduced survival and maturation of lymphocytes (mainly T-cells in humans)

Question 7

What is the cause of 50% of autosomal SCID and what is the consequence?

Answer 7

Mutations in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) leads to increased levels of toxic purine metabolites that injure lymphocytes undergoing active proliferation during maturation. Block in T cell maturation > B cell maturation.

Question 8

What is X-linked agammaglobulinemia?

Answer 8

Most common syndrome in blocked B cell maturation. Mutation in B cell tyrosine (Btk) gene leads to defective enzyme that normally helps in delivering biochemical signals that promote maturation of pre-B cells ==> severe decrease or absence of mature B cells and serum Igs. All male children are affected (notably arthritis.

Question 9

What is diGeorge syndrome?

Answer 9

Rare disorder involving incomplete development of the thymus and parathyroid glands leading to failure of T cell maturation. Patients can better with age since the small amt of thymic tissue does develop to support some T cell maturation.

Question 10

What are present therapies for SCID and caveats?

Answer 10

1) bone marrow transplant (most widely used)
2) IV immunoglobulin - antibodies isolated from healthy donors providing passive immunity (selective B cell defects)
3) replacement gene therapy for all congenital immunodeficiencies
CAVEAT: long-term effectiveness unknown, few patients have been tx with gene therapy

Question 11

What is X-linked hyper-IgM syndrome (defective B cell heavy chain class switching)?

Answer 11

Mutations in CD40L on CD4 T-cells so that binding to CD40 on B cells and macrophages is defective or doesn’t occur ==> results in IgM being the major serum antibody and severe deficiency in class switching in humoral immunity and T cell dependent macrophage activation in cell mediated immunity.

Question 12

What is common variable immunodeficiency?

Answer 12

Heterogenous group of disorders characterized by poor antibody response to infections and reduced serum levels of IgM, IgA. Underlying cause not understood; defects in B cell maturation and activation and defects in helper T cell fxn result in recurrent infections, autoimmune disease and lymphomas.

Question 13

What causes selective Ig isotype deficiencies and what is the consequence?

Answer 13

Cause not known, may be defect in B cell differentiation or T cell help. Results in reduced or absent selective isotypes or subtypes of Igs ==> susceptibility to bacterial infections or no clinical problems.

Question 14

What is bare lymphocyte syndrome?

Answer 14

Mutations in the transcription factors that induce MHC class II molecule expression ==> deficient expression of MHC class II leads to defective maturation and activation of CD4 T cells

Question 15

List SCID disorders.

Answer 15

1) X-linked SCID (mutation in gamma chain in cytokine receptor)
2) autosomal recessive SCID (ADA deficiency or PNP)
3) autosomal recessive SCID to other causes (defect in RAG genes)

Question 16

List B cell immunodeficiencies.

Answer 16

1) X-linked agammaglobulinemia (mutation in Btk)

2) Ig heavy chain deletions (chromosomal deletion in Ig heavy chain locus)

Question 17

List T cell immunodeficiencies.

Answer 17

DiGeorge syndrome (anomalous development of 3rd and 4th branchial pouches ==>hypoplastic thymus)

Question 18

List congenital immunodeficiencies w/defects in lymphocyte activation and effector fxn.

Answer 18

1) X-linked hyper-IgM syndrome (defect in CD40L on CD4 T cells)
2) selective Ig isotype deficiency (unknown cause in reduced isotypes)
3) bare lymphocyte syndrome (mutation in factors for gene expressing MHC class II)
4) defects in T cell receptor complex expression or signaling (mutation or deletion in genes encoding CD3, ZAP-70)

Question 19

What is chronic granulomatous disease?

Answer 19

Enzyme mutation of NADPH oxidase that catalyzes production of reactive oxygen species in lysosomes ==> PMNs and macrophages cannot kill microbes; recruitment of more macrophages and activation of T cells stimulates more macrophages ==> phagocytes accumulate around microbes forming collections resembling granulomas (chronic bacterial and fungal infections)

Question 20

What is leukocyte adhesion deficiency?

Answer 20

Mutations in genes encoding integrins and enzymes required for expression of ligands for selectins interferes with leukocyte slow rolling and arrest to vascular endothelium. Leukocytes cannot enter infected tissue.

Question 21

List complement deficiencies and consequences.

Answer 21

1) C3 deficiency results in severe recurrent gram neg bacterial infections; usu. fatal
2) C2 & C4 deficiencies result in immune-complex mediated disease resembling lupus
3) deficiencies in complement regulatory proteins (DAF) ==> excessive alternative pathway complement activation ==> complement mediated lysis of RBCs (paroxysmal nocturnal hemoglobinuria)
4) C5-C9 deficiencies ==> loss of membrane attack complex, susceptibility to Neisseria infections

Question 22

What is Chediak-Higashi syndrome?

Answer 22

Immunodeficiency in which the lysosomal granules of phagocytes and NK cells do not work normally leading to increased susceptibility to bacterial infections.

Question 23

Describe cause and symptoms of Wiskott-Aldrich syndrome.

Answer 23

X-linked disease w/mutation in the WASP gene that encodes a protein that binds to adapter molecules and cytoskeletal components in hematopoietic cells ==> small platelets and leukocytes that don’t develop normally and fail to migrate normally. Disease characterized by eczema, reduced blood platelets and immuodeficiency.

Question 24

What is ataxia-telangiectasia?

Answer 24

Mutation in a gene whose product may be involved in DNA repair leading to abnormal DNA repair ==> defective lymphocyte maturation. Characterized by ataxia, vascular malformations and immunodeficiency.

Question 25

List causes of secondary (acquired) immunodeficiency?

Answer 25

1) protein-calorie malnutrition (occurs mainly in under-developed countries)
2) cancer tx w/chemo agents and irradiation
3) immunosuppression to prevent organ/graft rejection
4) cancer mets to bone marrow
5) removal of spleen
6) HIV infection

Question 26

Describe the HIV.

Answer 26

Retrovirus that infects and destroys cells of the immune system, mainly CD4 T-cells. ds RNA within a protein core surrounded by a lipid envelope derived from infected host cells containing viral proteins. Viral RNA encodes structural proteins, enzymes and proteins that regulate transcription of viral genes and the viral life cycle.

Question 27

How does HIV infect a cell?

Answer 27

Envelope glycoprotein, gp120, binds to CD4+ T-cells and chemokine receptors CCR5 and CXCR4 on human cells. Viral membrane then fuses with host cell membrane and virus enters cytoplasm, uncoats by viral protease and its RNA is released. Virus reverse transcriptase synthesizes DNA copy of viral RNA which then incorporates itself into host cell’s DNA via integrase enzyme. Normal cytokine activation of cell can stimulate transcription of genes including HIV genome ==> production of viral RNA and proteins ==> core structure is formed, migration to cell membrane to acquire lipid envelop and mature virion buds from cell membrane into extracellular fluid ready to infect another cell

Question 28

What is provirus?

Answer 28

The integrated viral DNA copy of viral RNA produced by viral reverse transcriptase. Incorporates into host cell DNA via viral enzyme integrase. Can remain latent in infected cells for month or years.

Question 29

Describe pathogenesis of AIDS.

Answer 29

HIV establishes a latent infection that can be reactivated to produce infectious virus. After infection, there may be a brief, acute viremia and host responds as in any mild viral infection. The progressive depletion of CD4 T-cells after infection is d/t cytopathic effect of the virus = most reliable indicator of disease progression. Infected cells die during process of viral replication.

Question 30

Clinical course of HIV infection and AIDS.

Answer 30

1) early HIV infection - fever, malaise, subsides in a few days
2) latent phase - progressive loss of CD4+ T cells in lymphoid tissue and destruction of lymphoid tissue == decline in CD4 T-cell count
3) CD4+ T cell count susceptibility to opportunistic infections, AIDS dx
4) Advanced disease characterized by wasting syndrome w/significant loss of body mass due to altered metabolism and reduced caloric intake; development of dementia caused by infection of macrophage (microglia) in the brain.

Question 31

What is the cause of impairment in CD8+ T-cells and the antibody response in AIDS?

Answer 31

Defective CTL responses to viral antigens occurs b/c CD4+ T-cells are required for full CTL activation. Increased risk for bacterial infections occurs d/t impaired helper T-cell-antibody response to bacterial antigens.

Question 32

What are the 2 most common types of cancers in AIDS?

Answer 32

1) B-cell lymphomas caused by EBV

2) Kaposi’s sarcoma caused by HSV (tumor of small blood vessels)

Question 33

Describe the ineffective immune response in the attempt to control spread of virus and its pathological effects.

Answer 33

1) Abs and CTLs are produced early to limit the early acute HIV syndrome
2) Abs ineffective against envelope glycoproteins b/c virus rapidly mutates the region of gp120 (target of most Abs)
3) CTLs ineffective in killing infected cells b/c virus inhibits expression of class I MHC by infected cells
4) immune response to HIV may paradoxically promote spread of infection
5) antibody-coated viral particles bind to Fc receptors on macrophages and follicular DCs in lymphoid organs ==> ^ virus entry into these cells and creates additional reservoirs of infection
6) If CTLs are able to lyse infected cells ==> release of viral particles and infection of more cells

Question 34

What are current therapies and vaccination strategies?

Answer 34

1) control replication of HIV - block viral reverse transcriptase, protease and integrase (HAART, highly active antiretroviral tx). CAVEAT: Long-term tx effects unknown, problems with drug resistance and drug reservoirs of latent virus not eradicated
2) recent attempt involved combo of DNA immunization and recombinant poxviruses encoding several different HIV proteins

Question 35

What is the mutual activation of NK cells and macrophages? What deficiencies interfere with this?

Answer 35

1) IL-12 secreted by macrophages bind to IL-12 receptor on NK cells stimulating them to release IFN-y. IFN-y binds to IFN-y receptor on macrophages making them better at phagocytosis and secretion of pro-inflammatory cytokines. IL-12 secreted by macrophages also activate naive Th1 cells ==> Th1 cells release IFN-y to strengthen macrophage activation
2) IFN-y and IL-12 receptor deficiency leads to persistent intracellular bacterial infections; can be fatal