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p. 463. Ch. 20. AIDS and Other Immunodeficiencies. Primary: affects either adaptive or innate immunity inherited developmental Secondary: exposure to viruses and other agents Consequence: infection, life-threatening . p. 494. Severity depends on the number and type of

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p. 463

Ch. 20

slide2

Ch. 20. AIDS and Other Immunodeficiencies

Primary: affects either adaptive or innate immunity

inherited

developmental

Secondary:

exposure to viruses and other agents

Consequence: infection, life-threatening

Ch. 20

slide3

p. 494

Ch. 20

slide4

Severity depends on the number and type of

immune system aspects involved

Earlier developmental defects are more severe

Reticular dysgenesis- cells do not differentiate

during hematopoiesis

No lymphocytes

No phagocytes

Ch. 20

slide5

p. 495

Ch. 20

slide6

SCID: Severe Combined Immunodeficiency

Lymphoid cells are depleted

Thymus does not develop

Usually fatal without intervention

Ch. 20

slide7

Several causes of SCID

Lack of  chain of IL-2 receptor

also 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

slide8

p. 497

Ch. 20

slide10

p. 496

Ch. 20

slide11

Specialized immunodeficiencies

Phagocytic

fewer phagocytes or reduction in function

(chemotaxis, extravasation, killing)

Increased susceptibility to infections

S. aureus, S. pneumoniae, E. coli,

Pseudomonas, Candida, Aspergillus

Ch. 20

slide12

Neutrophil reduction

Neutropenia and worse

congenital or acquired

radiation or drugs

autoimmune syndromes (e.g., SLE)

can be temporary

neonatal neutropenia – Ab’s from mother

Ch. 20

slide13

Loss of function

LAD (leukocyte adhesion deficiency)

cells cannot adhere to endothelial cells

killer cells (CTL, NK) can’t adhere to

targets

Th and B cells can’t form conjugates

Defect in synthesis of beta-chain of integrin

adhesion molecules

Lazy-leukocyte syndrome

Ch. 20

slide14

Killing defects

Chronic granulomatous disease (X-linked)

(CGD)

Neutrophils can phagocytose bacteria

but can’t kill them

Defect in oxygen metabolism; can’t produce

H2O2

Ch. 20

slide15

Humoral deficiencies

X-linked agammaglobulinemia (XLA)

first immunodeficiency defined

Pre-B cells do not progress to mature B cells

all isotypes affected

Defect in Bruton’s tyrosine kinase

heavy-chain genes are rearranged but

light chain genes are not

Ch. 20

slide16

Diagnosed by serum electrophoresis

(gamma-globulin is severely reduced)

Treated with gamma-globulin

Still susceptible to pulmonary infections;

lack of secretory IgA

Ch. 20

slide17

X-linked hyper-IgM

Lack of CD40L on their Th cells

CD40-CD40L interaction required for B cell

response to T-dependent antigens

no class switching

no memory cells

no germinal centers in lymphoid organs

Ch. 20

slide18

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

slide19

p. 499

Ch. 20

slide20

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

slide21

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

slide22

DiGeorge syndrome

Lack of thymus (also defects in parathyroid

and aortic arches)

Diagnosis: low T cell count, no DTH,

decreased T cell activity

Treatment: fetal thymus grafts

Ch. 20

slide23

p. 500

Ch. 20

slide24

p. 503

Ch. 20

slide25

Nude mice: no CMI

Little antibody response

Death within 6 months

Can tolerate grafts

Thymus transplants can restore

immune competence

Ch. 20

slide26

To summarize, treatments for immunodeficiencies:

replacement of defective element:

* missing protein

* missing cell type or lineage

* missing or defective gene

Ch. 20

slide27

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

for agammaglobulinemia

Recombinant gamma-interferon for CGD

Recombinant IL-2 for AIDS patients

Recombinant 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

slide28

SCID mice- autosomal recessive mutation

no B or T cells, other cells functional

can be cured with bone marrow transplant

RAG knockout mice have also been developed

Knockout mice can be “designed” with specific

immune deficiencies

SCID-hu mouse is engrafted with human fetal liver,

adult thymus and lymph nodes

Ch. 20

slide30

Secondary immunodeficiencies

Acquired hypogammaglobulinemia

Immune suppression

Agent-induced immunodeficiency

AIDS, caused by HIV-1 retrovirus

Ch. 20

slide31

p. 505

Ch. 20

slide32

p. 506

Ch. 20

slide33

p. 508

Ch. 20

slide35

p. 509

Ch. 20

slide36

p. 510

Ch. 20

slide38

p. 511

Ch. 20

slide41

p. 512

Ch. 20

slide42

p. 513

Ch. 20

slide43
Ch. 20

p. 516

slide45

p. 515

Ch. 20

slide46

p. 516

Ch. 20

slide47

Categories of drugs – p. 517

Reverse transcriptase inhibitors

nucleoside analogs

nonnucleoside analogs

Protease inhibitors

Fusion inhibitor

Lots of drugs, lots of side effects

Combinations lower viral load

Ch. 20

slide48

p. 517

Ch. 20

slide49

p. 519

Ch. 20

slide50

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 therapy

less extreme: antibody therapy, drugs

Ch. 20