3Primary immune deficiency diseases. Lymphocyte development and sites of block in primary immune deficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA)= adenosine deaminase;) CD40L,= (CD40 ligand ((also known as CD154); CVID=common variable immunodeficiency; SCID,=severe combined immunodeficiency
4Immunodeficiency syndrome Primary Immunodeficiency: -( Rare )* Early onset, usually between 6 months & 2 years of age* Recurrent infections* Classification* B-cell deficiencies: -1-X-linked agammaglobulinemia of Bruton2-Common variable immunodeficiency3-Isolated IGA deficiency
6X-linked Agammaglobulinaemia of Bruton Absent or markedly decreased concentration of all classes of Ig* Affecting boys (X-linked disease)* Symptoms appear after 6 months of age* Typically there is increase incidence of otitis media, skin & respiratory infections caused byH. influenzae, S. pneumoniae, or S. aureus
7Isolated IgA immunodeficiency: * Most common type accounts for 1/600 individuals* Either familial or acquired (in association with toxoplasmosis & measles)* Many of these men & women are asymptomatic* Increase incidence of respiratory, GIT & urogenital tract infections* Increase incidence of autoimmune diseases esp. SLE & rheumatoid arthritis* Defect in differentiation of IgA B-cells
8DiGeorge syndrome (Thymic hypoplasia) * T-cell deficiency due to the failure of development of thymus* No cell-mediate response* Part of CATCH 22 syndrome (Cardiac abnormality, T-cell deficiency, cleft palate, hypocalcemia)due to deletion of chromosome 22
9Secondary IDs: These states arising as a complication of Chronic infection ,old age,Chronic malnutrition,Wide spread malignancyChronic renal failureSide effects of immune suppression,irradiation ,or chemotherapy for cancer or other autoimmune diseases .
10Acquired Immune Deficiency Syndrome AIDSAcquired Immune Deficiency Syndrome( Modern plague)it is a retroviral disease caused by HIV & characterized by immunsuppression leading to : Opportunistic infections Secondary neoplasms Neurologic manifestations.
11Acquired immunodeficiency syndrome AIDS is a retroviral (RNA virus) disease characterized by: -1-Profound immunosuppression that leads to opportunistic infections2- Secondary neoplasms3- Neurologic manifestationsDespite dramatic improvements in drug therapy, the true mortality rate is likely to approach 100 %In United states, AIDS is the leading cause of death in men between year of age & third leading cause of death in women
12Epidemiology * First described in United States * United States has the majority of the reported cases* Infection in Asia & Africa now is large & expanding* Adults at risk for developing AIDS are: -1-Homosexual men constitute by far the largest group, accounting for 57 % of reported cases2-Intravenous drug abusers compose the next largest group accounting about 25 %3-Hemophiliacs esp.. before 1985, make up 0.8 % of all cases
13Epidemiology: -4-Recipients of blood & blood components who are not hemophiliac, account for 1.2 % of cases5-Heterosexual contacts constitute 10 % of all cases6-Approximately 6 % of cases, the risk factors can’t be determined7- Newborn of infected mothersClose to 2 % of all AIDS cases occur in pediatric population, more than 90 % result from transmission of virus from infected mother to her baby. The remaining 10 % are hemophiliacs or received blood & blood products before 1985
14Etiology: -* HIV is human retrovirus belonging to the lentivirus family* 2 genetically different but related forms of HIV called HIV-1 & HIV-2* HIV-1 is most common type associated with AIDS in U.S, Europe & central Africa* P24 (major caspid protein) is the most readily detected viral Ag & target for Ab that is used for the diagnosis of AIDS* gp120 & gp41 are viral envelope which are critical for infection* HIV-1 subdivided into; M & TM form is most common form worldwide
16Pathogenesis:* 2 major targets of HIV:A-Immune systemB-CNS
17A) Immunopathogensis of HIV disease: * Profound immunosuppression primary affectingcell-mediate immunity* Severe loss of CD4 T-cells & impairment in thefunction of surviving helper T cell* Macrophage & dendritic cells are also target of HIVinfection* For infection, binding of the virus to CD4 is not sufficient, therefore HIV gp120 must also bind to co-receptor (CCR5 & CXCR4) for entry into the cells
18Figure 5-31 Molecular basis of HIV entry into host cells Figure 5-31 Molecular basis of HIV entry into host cells. Interactions with CD4 and a chemokine receptor ("coreceptor).
19Figure 5-32 Pathogenesis of HIV infection Initially, HIV infects T cells & macrophages directly or is carried to these cells by Langerhans cells.Viral replication in the regional lymph nodes leads to viremia & widespread seeding of lymphoid tissue.The viremia is controlled by the host immune response & the patient then enters a phase of clinical latency.During this phase, viral replication in both T cells and macrophages continues unabated, but there is some immune containment of virus.There continues a gradual erosion of CD4+ cells by productive infection.Ultimately, CD4+ cell numbers decline & patient develops clinical symptoms of full-blown AIDSMacrophages are also parasitized by the virus early; they are not lysed by HIV & they transport the virus to tissues, particularly the brain.
21Figure 5-33 Mechanisms of CD4 cell loss in HIV infection Figure 5-33 Mechanisms of CD4 cell loss in HIV infection. Some of the principal known and postulated mechanisms of T-cell depletion after HIV infection are shown
22A) Immunopathogensis of HIV disease: HIV strains can be classified into 2 groups on the basis of their ability to infect macrophage & CD4 T-cellM-tropic which can infect both monocytes / macrophages & freshly isolated peripheral T-cellT-tropic which infect only T-cell* M-tropic strain use CCR5 receptor, whereas * T-tropic strain bind to the CXCR4 receptor which only present in T-cell
23B) Pathogenesis of CNS involvement: - * Nervous system is a major target of HIV infection* Macrophages & micoglial cells are the predominant cell type infected with HIV* Infection transmitted to CNS through monocytes & are almost exclusively of M-tropic type* HIV does not infect Neurons* Injury to the nervous system occurs indirectly by viral products & soluble factors produced by macrophage / microglial cells e.g., IL1, TNF & IL6
24Natural history of HIV infection: * 3 phases can be recognized-Early acute phase-Middle chronic phase-Final crisis phase
25Natural history of HIV infection: .1-Early acute phase: -* Represent the initial response of immunocompetent adult to HIVClinically is associated with self limited acute illness that develop in % of HIV infected patients such as rash, cervical lymph-adenopathy, diarrhea & vomiting which persist for 3-6 weeks
26Natural history of HIV infection 2-Middle chronic phase: -There is continued HIV replication predominantly in lymphoid tissue* Patient are either asymptomatic or develop persistent generalized lymphadenopathy* Many patients have minor opportunistic infection such as thrush or herpes zoster
27Natural history of HIV infection .3-Final crisis phase: -* Characterized by break down of host defense* Dramatic increase in plasma virus & clinical disease* Patients present with a long standing fever (> 1 month), fatigue, weight loss & diarrhea* CD4 cell count is reduced below 500 cell / ml* Serious opportunistic infection, secondary neoplasm or clinical neurological diseases, these called AIDS defining conditions
28Opportunistic infections: - 1) Pneumonia caused by pneumocystis carinii, about 50 % of AIDS patients develop this infection2) Candida albicans infections of mouth, esophagus, vagina & lungs3) cytomegalovirus enteritis & pneumonia & retinitis4) Atypical mycobacterial infection (esp. M. avium-intracellulare) of G.I.T5) Herpes simplex infection of mucocutanous areas
29Most Common Neoplasms associated with AIDS 1)Kaposi Sarcoma: -* Vascular tumor* Most common tumor in AIDS patients2)Non-Hodgkin lymphoma: -* 120 times more risk in AIDS patients than in general population
30Most Common Neoplasms associated with AIDS: 3)Carcinoma of uterine cervix4)Squamous cell carcinoma of the skin5) Hodgkin disease
31Clinical Symptoms HIV CD4 Activation by cytokines TNF,IL-6 Pathogenesis : The major target of HIV infection are:tImmune systemCNSHIVCD4Activation bycytokines TNF,IL-6Viraemia & wide spreadseeding of lymphoid tissueCD4BuddingA.g. stimulationCytokine stimulationExtensive ViralReplication (HIV Reservoir)Follicular dendritic cell(HIV reservoir)CD4Extensive viral replication&CD4+T cell lysis & lossOpportunistic inf.&neoplasmsClinical SymptomsTransport tobrain & lung
32THE MULTIPLE EFFECTS OF CD4+CELL AFTER HIV INFECTION: MacrophageCD4CD8NKB-cell*↓ CytotoxicAbility*↓chemotaxis*↓IL-1 secretion*poor a.g.presentation*↓ResponseTo solublea.g.*↓Cytokinesecretion↓ IgProductionto new a.g.↓Killing ofTumour cells↓Specificcytotoxicity