p. 463

Ch. 20

p. 463

Ch. 20

Ch. 20. AIDS and Other Immunodeficiencies

Primary: affects either adaptive or innate immunityinheriteddevelopmental

Secondary:exposure to viruses and other agents

Consequence: infection, life-threatening

Ch. 20

p. 494

Ch. 20

Severity depends on the number and type ofimmune system aspects involved

Earlier developmental defects are more severe

Reticular dysgenesis- cells do not differentiateduring hematopoiesis

No lymphocytes

No phagocytes

Ch. 20

p. 495

Ch. 20

SCID: Severe Combined Immunodeficiency

Lymphoid cells are depleted

Thymus does not develop

Usually fatal without intervention

Ch. 20

Several causes of SCID

Lack of chain of IL-2 receptoralso affects signaling through IL-4,-7,-9,-15

ADA (adenosine deaminase) deficiency

Defects in signal transduction or transcription

Deficiencies in MHC Class I or Class II synthesis

Ch. 20

p. 497

Ch. 20

Ch. 20

p. 496

Ch. 20

Specialized immunodeficiencies

Phagocytic

fewer phagocytes or reduction in function(chemotaxis, extravasation, killing)

Increased susceptibility to infectionsS. aureus, S. pneumoniae, E. coli,Pseudomonas, Candida, Aspergillus

Ch. 20

Neutrophil reduction

Neutropenia and worsecongenital or acquiredradiation or drugsautoimmune syndromes (e.g., SLE)can be temporaryneonatal neutropenia – Ab’s from mother

Ch. 20

Loss of function

LAD (leukocyte adhesion deficiency)

cells cannot adhere to endothelial cellskiller cells (CTL, NK) can’t adhere to

targetsTh and B cells can’t form conjugates

Defect in synthesis of beta-chain of integrinadhesion molecules

Lazy-leukocyte syndrome

Ch. 20

Killing defects

Chronic granulomatous disease (X-linked)(CGD)

Neutrophils can phagocytose bacteria but can’t kill them

Defect in oxygen metabolism; can’t produceH2O2

Ch. 20

Humoral deficiencies

X-linked agammaglobulinemia (XLA)first immunodeficiency defined

Pre-B cells do not progress to mature B cellsall isotypes affected

Defect in Bruton’s tyrosine kinaseheavy-chain genes are rearranged butlight chain genes are not

Ch. 20

Diagnosed by serum electrophoresis(gamma-globulin is severely reduced)

Treated with gamma-globulin

Still susceptible to pulmonary infections;lack of secretory IgA

Ch. 20

X-linked hyper-IgM

Lack of CD40L on their Th cells

CD40-CD40L interaction required for B cellresponse to T-dependent antigens

no class switching no memory cells no germinal centers in lymphoid organs

Ch. 20

Late-onset problems: various possible causes

Inability to switch from membrane-bound to secreted form

Structural defect in antibody

B cells do not respond to cytokines

Ch. 20

p. 499

Ch. 20

Selective IgA deficiency very common (1:600-800)

Asymptomatic or

Recurrent GI and respiratory infections

Tend to have more allergic reactions

Complement deficiencies result in either:Immunodeficiency (infections) and/or immune complex disease

Ch. 20

Cell-mediated deficiencies

Increased susceptibility to viral, protozoan,fungal diseases

Usually innocuous microbes can become life-threatening

Tend to affect humoral responses, too

Ch. 20

DiGeorge syndrome

Lack of thymus (also defects in parathyroidand aortic arches)

Diagnosis: low T cell count, no DTH, decreased T cell activity

Treatment: fetal thymus grafts

Ch. 20

p. 500

Ch. 20

p. 503

Ch. 20

Nude mice: no CMI

Little antibody response

Death within 6 months

Can tolerate grafts

Thymus transplants can restoreimmune competence

Ch. 20

To summarize, treatments for immunodeficiencies:replacement of defective element:

* missing protein* missing cell type or lineage * missing or defective gene

Ch. 20

Thus, pooled human gamma-globulin (Ab’s) for agammaglobulinemia

Recombinant gamma-interferon for CGDRecombinant IL-2 for AIDS patientsRecombinant ADA for ADA-deficient SCID patients

Gene therapy for ADA-deficiency and CGD, p67phox-deficiency: CD34+ stem cells from pt. transfected with normal copy of defective gene)

Cell replacement: bone marrow transplantation CD34+ stem cells from HLA-matched donor

Ch. 20

SCID mice- autosomal recessive mutationno B or T cells, other cells functionalcan be cured with bone marrow transplant

RAG knockout mice have also been developed

Knockout mice can be “designed” with specificimmune deficiencies

SCID-hu mouse is engrafted with human fetal liver,adult thymus and lymph nodes

Ch. 20

SCID-hu Mice – discussed on p. 504

Ch. 20

Secondary immunodeficiencies

Acquired hypogammaglobulinemia

Immune suppressionAgent-induced immunodeficiency

AIDS, caused by HIV-1 retrovirus

Ch. 20

p. 505

Ch. 20

p. 506

Ch. 20p. 508

Ch. 20

Ch. 20

p. 509

Ch. 20

p. 510

Ch. 20

Ch. 20

p. 511

Ch. 20

Ch. 20

Ch. 20

p. 512

Ch. 20

p. 513

Ch. 20 p. 516

Ch. 20

Ch. 20p. 515

Ch. 20

p. 516

Ch. 20

Categories of drugs – p. 517

Reverse transcriptase inhibitorsnucleoside analogsnonnucleoside analogs

Protease inhibitors

Fusion inhibitor

Lots of drugs, lots of side effects

Combinations lower viral load

Ch. 20

p. 517

Ch. 20

p. 519

Ch. 20

Summary

Immune deficiencies are either primary(genetic, developmental)

Or acquired (infection, radiation, HIV, immunosuppressive treatment)

Classified by type of cell(s) compromised

Treatments:replacement: bone marrow, gene therapyless extreme: antibody therapy, drugs