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Lecture 4. Primary immune deficiency diseases. Lymphocyte development and sites of block in primary immune deficiency diseases. The affected genes are.

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Presentation on theme: "Lecture 4. Primary immune deficiency diseases. Lymphocyte development and sites of block in primary immune deficiency diseases. The affected genes are."— Presentation transcript:

1 Lecture 4


3 Primary 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

4 Immunodeficiency 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 Bruton 2-Common variable immunodeficiency 3-Isolated IGA deficiency

5 Primary Immunodeficiency * T-cell deficiencies: - 1-Hyper IGM syndrome 2-DiGeorge syndrome * Severe combined immunodeficiency

6 –X-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 by H. influenzae, S. pneumoniae, or S. aureus

7 Isolated 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

8 DiGeorge 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

9 Secondary IDs: These states arising as a complication of Chronic infection, old age, Chronic malnutrition, Wide spread malignancy Chronic renal failure Side effects of immune suppression,irradiation, or chemotherapy for cancer or other autoimmune diseases.

10 ( Modern plague) it is a retroviral disease caused by HIV & characterized by immunsuppression leading to : 1.Opportunistic infections. 2.Secondary neoplasms. 3.Neurologic manifestations.

11 Acquired immunodeficiency syndrome AIDS is a retroviral (RNA virus) disease characterized by: - 1- Profound immunosuppression that leads to opportunistic infections 2- Secondary neoplasms 3- Neurologic manifestations Despite 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

12 Epidemiology * 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 cases 2-Intravenous drug abusers compose the next largest group accounting about 25 % 3-Hemophiliacs esp.. before 1985, make up 0.8 % of all cases

13 Epidemiology: - 4-Recipients of blood & blood components who are not hemophiliac, account for 1.2 % of cases 5-Heterosexual contacts constitute 10 % of all cases 6-Approximately 6 % of cases, the risk factors can t be determined –7- Newborn of infected mothers Close 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

14 Etiology: - * 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 & T M form is most common form worldwide


16 Pathogenesis: * 2 major targets of HIV: –A-Immune system –B-CNS

17 A) Immunopathogensis of HIV disease: * Profound immunosuppression primary affecting cell-mediate immunity * Severe loss of CD4 T-cells & impairment in the function of surviving helper T cell * Macrophage & dendritic cells are also target of HIV infection * 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

18 Figure 5-31 Molecular basis of HIV entry into host cells. Interactions with CD4 and a chemokine receptor ("coreceptor).

19 Figure 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 AIDS Macrophages are also parasitized by the virus early; they are not lysed by HIV & they transport the virus to tissues, particularly the brain.


21 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

22 A) Immunopathogensis of HIV disease : HIV strains can be classified into 2 groups on the basis of their ability to infect macrophage & CD4 T-cell 1.M-tropic which can infect both monocytes / macrophages & freshly isolated peripheral T-cell 2.T-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

23 B) 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

24 Natural history of HIV infection: * 3 phases can be recognized -Early acute phase -Middle chronic phase -Final crisis phase

25 Natural history of HIV infection:. 1- Early acute phase: - –* Represent the initial response of immunocompetent adult to HIV Clinically 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

26 Natural 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

27 Natural 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

28 Opportunistic infections : - 1) Pneumonia caused by pneumocystis carinii, about 50 % of AIDS patients develop this infection 2) Candida albicans infections of mouth, esophagus, vagina & lungs 3) cytomegalovirus enteritis & pneumonia & retinitis 4) Atypical mycobacterial infection (esp. M. avium- intracellulare) of G.I.T 5) Herpes simplex infection of mucocutanous areas

29 Most Common Neoplasms associated with AIDS 1)Kaposi Sarcoma: - * Vascular tumor * Most common tumor in AIDS patients 2)Non-Hodgkin lymphoma: - * 120 times more risk in AIDS patients than in general population

30 Most Common Neoplasms associated with AIDS: 3) Carcinoma of uterine cervix 4) Squamous cell carcinoma of the skin 5 ) Hodgkin disease

31 Pathogenesis : The major target of HIV infection are:t Immune system CNS CD4 HIV Viraemia & wide spread seeding of lymphoid tissue Follicular dendritic cell (HIV reservoir) CD4 Activation by cytokines TNF,IL-6 Budding Clinical Symptoms Extensive Viral Replication (HIV Reservoir) A.g. stimulation Cytokine stimulation Extensive viral replication &CD4+T cell lysis & loss Opportunistic inf. &neoplasms Transport to brain & lung CD4

32 THE MULTIPLE EFFECTS OF CD4+CELL AFTER HIV INFECTION: HIV CD4 CD8B-cell NK Macrophage * Response To soluble a.g. * Cytokine secretion Specific cytotoxicity Killing of Tumour cells Ig Production to new a.g. * Cytotoxic Ability * chemotaxis * IL-1 secretion *poor a.g. presentation

33 II. pathogenesis of CNS involvement: HIV TNF-α IL-1 IL-6NO microglia

34 KAPOSI SARCOMA CD4 cell Infected B-cell Cytokines Proliferation & Angiogenesis HIV KSHV (HHV-8) Mesenchymal cells tat-protein Kaposi Sarcoma

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