Kuby IMMUNOLOGYSixth Edition

Chapter 20AIDS and Other

Immunodeficiencies

Copyright © 2007 by W. H. Freeman and Company

Kindt • Goldsby • Osborne

Immune dysfunction

• Autoimmunity

• Immunodeficiency – Primary immunodeficiency : results from

genetic or developmental defects– Secondary immunodeficiency : results from

acquired agents, such as HIV-1, chemotherapeutic agents, immunosuppressants.

Primary immunodeficiency

The loci on the X-chromosome in X-linked immunodeficiency diseases

Lymphoid immunodeficiency

• B-cell immunodeficiency – 성숙한 순환성 B 세포 , 형질세포 그리고 글로블린의 결핍 .– Recurrent extracellular bacterial infections, but normal immunity

to intracellular bacteria, fungal or viral infections– Especially susceptible to encapsulated bacteria, such as

staphylococci, streptococci, and pneumococci• T-cell immunodeficiency

– Affect both humoral and cell-mediated responses– No DTH and cytotoxicity responses– Susceptibile to intracellular bacteria, viral, protozoan and fungal

infections : Candida albicans, Pneumocystisis crinii, Mycobacteria

Severe Combined Immunodeficiency (SCID)

• T-cell defects and some patients also have B- or NK cell defects• Screening test for SCID in neonates – assay excised DNA circle in

blood cells• Clinical features

– Low number of circulating lymphocytes– No thymus development, no proliferation of lymphocytes by mitogens.– Recurrent infections in infants : chronic diarrhea, pneumonia, and skin,

mouth, and throat lesions, and other opportunistic infections.

• Fatal in the early years of life.• B-cell lineage defects is not evident in the first

few months because of mother antibodies (transplacental transfer and milk).

• Very compromised immune system-even live-attenuated vaccines (Sabin polio vaccine) can cause infection and disease.

• Sterile environment can prolong life span.• The cause of SCID (survey of 170 patients)

– 78 cases (46%) have IL-2R deficiency: defects in signaling of IL-2, 4, 7, 9 and 15.

– Jak-3 (11), IL-7R (17)

SCID

Distribution of genetic defects in 170 cases of SCID tracked over 35 years

Cellular phenotypes related to different genetic defects observed in SCID

* Adenosine deaminase (ADA) : convert adenosine into inosine. ADA deficiency (28 cases) - cause adenosine accumulation distort purine metabolism block DNA synthesis. - results in defects in T, B, and NK cells. * Recombinase activating genes (RAG-1/2) deficiency (5 cases) - impair TCR and Ig gene rearrangements.* ZAP-70 (tyrosine kinase) deficiency - TCR signaling molecule. - normal Ig and CD4 T-cell number, but nonfunctional.* MHC II deficiency – bare lymphocyte syndrome* TAP deficiency –results in MHC I deficiency

Defects in cell interaction and signaling can cause SCID

A child with DiGeorge syndrome showing characteristic ear dysplasia of ears and mouth and abnormally long distance between the eyes.

Wiskott-Aldrich Syndrome (WAS)

• X-linked: sialophorin (CD43 gene deficiency)

• Symptoms increase with age, resulting fatal infection or malignancy

• Recurrent infections, loss of humoral and cell-mediated response, thrombocytopenia, eczema

Thymus defects– DiGeorge syndrome (congenital thymic aplasia

선천성흉선무형성증 )• Developmental defect

• Deletion of a region of chromosome 22 during embryo stage

• Immuno deficiency and facial abnormalities, hypoparathyroidism, heart disease

• Also called as “the third and fourth pharyngeal pouch syndrome”)

• Short life span. No T- and B-cell responses.

– Thymic hypoplasia (Nezelof syndrome)• Congenital disease. vesti

• T-cell defect, some patients have normal B-cells

• Chronic diarrhea, viral and fungal infections.

• Ataxia Telangiectasia– Difficulty in maintaining balance (Ataxia) and broken

capillaries in the eyes (Telangiectasia 모세혈관확장증 )

– Defect in cell cycle kinase

– IgA and IgE deficiency

• Complement defects– Properdin (stabilization of C3 convertase),

mannose-binding protein (MBL) defect increases susceptibility to bacteria or fungi infections.

• Interferon-Gamma-Receptor Defect– Susceptible to mycobacteria infections– IL-12 receptor, NFkB, IKK deficiency show

similar symptoms

X-linked Agammaglobulinemia (X-LA)

• Also called as Brutons hypogammaglobulinemia• Low IgG, no peripheral B-cells• Recurrent bacterial infections beginning at about 9 months

of age• Defects in Bruton’s tyrosine kinase (Btk) which is a B-cell

signal transduction molecule. • B-cells remain at pre-B stage : H chain but not L chain

rearrangements

X-Linked Hyper-IgM Syndrome (XHM)

• Deficiency of IgG, IgA, IgE and elevated levels of IgM

• High levels of auto-antibody to neutrophils, platellets and RBCs

• CD40L deficiency:CD40-CD40L interaction is required for B-T-cell interaction

• No class switching of B-cells without T-cell help.

• Common Variable Immunodeficiency (CVI) – Low number of plasma cells and low levels of Ig

– No differentiation of B cells to plasma cells

• Hyper-IgE syndrome (Job Syndrome)– Skin abscesses, recurrent pneumonia, eczema, high IgE

levels

– Facial abnormalities, bone fragility

– HIES gene : dominant, located at chromosome 4

• Selective Deficiencies of Ig classes– IgA deficiency : asymptomatic or recurrent respiratory

and genitourinary tract infections. IgG2 or IgG4 may also be absent

– IgM deficiency ; rare, severe meningococcus ( 수막염 ) infections

Immunodeficiencies of the myeloid lineage

• Reduction in Neutrophil count– Granulocytopenia or neutropenia : <1500/ul– Congenital neutropenia : due to genetic defect in

myeloid stem cell differentiation (G-CSF deficiency)– Acquired neutropenia

• Radiation, chemotherapeutic agents• Sjögren’s syndrome : auto-antibody destroy neutrophils • Bacterial and viral infection cause transient neutropenia

• Chronic Granulomatous Disease (CGD)– Defect in generating hydrogen peroxide– No killing of phagocytosed bacteria, lowered APC

function – Caused by cyt b558, or phagosome oxidase defect– Treatment by administration of IFN- or gene therapy

• Chediak-Higashi syndrome– LYST protein defect : targeting of proteins to secretory

lysosomes is impaired

– Recurrent bacterial infections, partial oculo-cutaneous albinism, infiltration of lymphoid organs by lymphocytes

– Giant granules in phagocytes with no bacterial killing activity

• Leukocyte Adhesion Deficiency (LAD)– Immune cells do cellular interaction using integrin family

proteins

– LFA-1(CD11a), Mac-1(CD11b), gp150/95(CD11c) have a common chain as

– Deficiency of chain : susceptible to G+, G- bacteria and fungi

Treatments of immunodeficiency disorders

Replacement of a missing protein– Agammaglobuninemia: pooled human gamma

globulin– Humanized monoclonal antibodies to specific

antigen– Recombinant cytokines : IL-2, IFN-g, ADA

Replacement of a missing cell type or lineage- Bone marrow transplantation: HLA matching is

require- HLA-mismatched bone marrow : Depletion of T-

cells and enrichment of CD34+ stem cells from donor bone marrow cells decrease GVHD

Replacement of a missing gene- Gene therapy : clinical trial of ADA, p67phox

gene resulted disease control for 6-18 months- Isolation of bone marrow stem cells from

patients transfection with a normal gene return to patients

- Side effects : leukemia

Experimental models of immunodeficiency

Nude (Athymic) Mice

• Nude mice– nu/nu mice : hairless, vestigial thymus– no TCR, but TCR T-cells– maintained under pathogen-free conditions

• specific pathogen-free (SPF) facility : sterilization of food, water, cages and bedding and air filtration

– no cell-mediated response and antibody response to most antigens

– tolerate xenograft• growth of hybridoma• growth of human cancer cells• growth of human stem cells

• The SCID mouse– only pre-B and T-cells, no lymphocytes in

thymus, spleen, lymph nodes or gut tissues.– Human bone marrow cells can be established in

SCID mice HIV infection study possible

• RAG KO mice– recombination activating enzyme gens (RAG-1,

2)

AIDS and other Acquired of Secondary Immunodeficiencies

• Acquired hypogammabulinemia

• Agents-induced immunodeficiency ; corticosteroids, cyclosporin A, cytotoxic drugs, radiation treatments induce immunodeficiencies.

Death rates in people ages 25-44 years in USA

Acquired Immunodeficiency Syndrome

• The first report :1981 in USA– unusual infections : opportunistic Pneumonia carinii infection

– rare skin tumor : Kaposi’s sarcoma

– deficiency in cellular immunity and CD4+ T cells

– The most of patients are homosexual males, heterosexual promiscuous heterosexual males and females, iv drug users, blood or blood product receivers, infants born to HIV-infected mothers.

– USA: 524000 death and 1 million infected

– World-wide• 40.3 million AIDS patient

• 4.9million new infection in 2005

HIV-1 Transmission• HIV-1 is contained in milk, blood, semen or vaginal

fluid of infected person• sexual intercourse

– heterosexual contact makes 75% of HIV-1 transmission

– increase of transmission probability : anal sex, the presence of sexually transmitted diseases (STDs)

– Male circumcision reduces the risk of males and females HIV-1 infections

– The use of condoms are highly recommended

• receipt of infected blood or blood products– HIV test of blood supply began in 1985

• mothers to infants– 30% of infants born to HIV-infected mothers

are infected by virus.– anti-viral agents (nevirapine, zidovudine) given

to mothers decrease the probability of infant virus infections.

HIV-1• retrovirus

– Genome is two single strand RNA– reverse transcriptase (RT) transcribes genome

RNA into DNA copy (provirus) – provirus is integrated into the cell genome– human lymphotrophic virus 1 (HLTV-1) is also

retrovirus causing leukemia or neurologic diseases in some infected people

– simian immunodeficiency virus (SIV) in monkey is similar to HIV-1

– HIV-1 does not replicate in other animals except chimpanzees which can be infected but does not develop AIDS.

– SCID mouse reconstituted with human lymphoid organs can be infected by HIV-1 and develop AIDS.

– For HIV-1 infection, receptors and other factors are required.

Prevention of infant HIV infection by anti-retroviral treatment

Mural showing mother and child on an outside wall of Mulago Hospital Complex in Kampala, Uganda.

700,000 infants are infected with HIV through mother to child transmission in 2005.

Treatments in USA : administration of zidovudine (AZT) into infected mothers for several months prior to delivery and treatments her infant for 6 week after birth.Disadvantage in cost and timing.

Single dose of nevirapine (Viramune) therapy.single dose of nevirapine to mothers at the onset of

labor and to infants at 24-30 hr after birth.Results (%of infection)

16 weeks 18 months Control: 40.2% zidovudine : 22.1% 25.8%Nevirapine : 13.5% 15.7%

Cross-sectional diagram of HIV virion.

72/virionReceptor for CD4 T-cells

Two copies of ss RNA

EM of HIV virions magnified X200,000

Buds on the surface of HIV-infected T-cells represent newly formed viral particles

Genetic organization of HIV-1

Functions of HIV-1 proteins

In vitro studies revealed the HIV-1 replication cycle

• HIV-1 infect human T-cells in culture.• viral attachment and entry into target cells

– gp120 binds to CD4• gp120-CD4, cell adhesion molecules leads to T-cell-T-cell fusion.• cell fusion makes giant multinuclear cells (syncytia)

– co-receptors are required : • T-cell—CXCR4• monocytes – CCR5

– reverse transcription• RT makes cDNA and dsDNA

– Movement into nucleus– Integrase integrate viral dsDNA into human genome

HIV-1 infection leads to opportunistic infections

AIDS: # of CD4 T cells <200/ulno DTH responseopportunistic infections

Thrush

• period between HIV-1 infection and AIDS:9-12 years• Acute, chronic, AIDS phase• Acute phase

– Primary infection goes unnoticed – some people’s symptoms are fever, lymphadenopathy, rash– immune activation : DC takes up virus and moves to lymph nodes and

present antigen to T-cells.– rise of HIV-1 in blood, drop in the # of CD4 T cells

• chronic phase– constant T-cell number– virus replicate 109 virions/day but viral load is kept constant by antibody

and CD8 T-cells – lymph node cells are infected by virus– gradual depletion of CD4 T-cells in peripheral tissues– infected T-cells are rapidly killed : half life 1.5 days– some infected T-cells are not lysed, but keep them in provirus state.

• AIDS phase– the most common opportunistic infection in AIDS patients : C. albicans ,

P.carinii– loss of DTH function– high levels of serum IgA and IgE– some people develop neurologic symptoms :AIDS dementia

Passage of HIV-1 (green dots) between DC and T-cells during interaction

Depletion of CD4 T-cells in GI tract of AIDS patient

Therapeutic agents against HIV-1

• no vaccines available• Pharmacological drugs

– RT inhibitors: nucleoside analogue and others– Protease inhibitors– Fusion inhibitors

• The current treatment for AIDS is combination therapy– Highly active anti-retroviral therapy (HAART)

• two nucleoside analogue and one protease inhibitor

• The cure of AIDS is difficult because of latently infected CD4 T-cells and macrophages