20장 aids and other immunodeficiencies
TRANSCRIPT
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Kuby IMMUNOLOGYSixth Edition
Chapter 20AIDS and Other
Immunodeficiencies
Copyright © 2007 by W. H. Freeman and Company
Kindt • Goldsby • Osborne
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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.
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Primary immunodeficiency
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The loci on the X-chromosome in X-linked immunodeficiency diseases
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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
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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.
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• 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
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Distribution of genetic defects in 170 cases of SCID tracked over 35 years
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Cellular phenotypes related to different genetic defects observed in SCID
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* 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
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Defects in cell interaction and signaling can cause SCID
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A child with DiGeorge syndrome showing characteristic ear dysplasia of ears and mouth and abnormally long distance between the eyes.
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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
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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.
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• Ataxia Telangiectasia– Difficulty in maintaining balance (Ataxia) and broken
capillaries in the eyes (Telangiectasia 모세혈관확장증 )
– Defect in cell cycle kinase
– IgA and IgE deficiency
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• 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
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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
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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.
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• 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
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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
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• 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
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• 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
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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
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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
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Experimental models of immunodeficiency
Nude (Athymic) Mice
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• 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
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• 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)
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AIDS and other Acquired of Secondary Immunodeficiencies
• Acquired hypogammabulinemia
• Agents-induced immunodeficiency ; corticosteroids, cyclosporin A, cytotoxic drugs, radiation treatments induce immunodeficiencies.
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Death rates in people ages 25-44 years in USA
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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
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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
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• 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.
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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
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– 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.
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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.
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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%
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Cross-sectional diagram of HIV virion.
72/virionReceptor for CD4 T-cells
Two copies of ss RNA
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EM of HIV virions magnified X200,000
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Buds on the surface of HIV-infected T-cells represent newly formed viral particles
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Genetic organization of HIV-1
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Functions of HIV-1 proteins
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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
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HIV-1 infection leads to opportunistic infections
AIDS: # of CD4 T cells <200/ulno DTH responseopportunistic infections
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• 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
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Passage of HIV-1 (green dots) between DC and T-cells during interaction
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Depletion of CD4 T-cells in GI tract of AIDS patient
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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
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