IMMUNE DEFICIENCY DISEASES Lecture 4

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

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

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

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

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

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

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 .

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

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 25-44 year of age & third leading cause of death in women

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

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

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

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

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

Figure 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).

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.

Figure 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

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 M-tropic which can infect both monocytes / macrophages & freshly isolated peripheral T-cell 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

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

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

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 50-70 % of HIV infected patients such as rash, cervical lymph-adenopathy, diarrhea & vomiting which persist for 3-6 weeks

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

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

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

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

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

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

THE MULTIPLE EFFECTS OF CD4+CELL AFTER HIV INFECTION: Macrophage CD4 CD8 NK B-cell *↓ Cytotoxic Ability *↓chemotaxis *↓IL-1 secretion *poor a.g. presentation *↓Response To soluble a.g. *↓Cytokine secretion ↓ Ig Production to new a.g. ↓Killing of Tumour cells ↓Specific cytotoxicity

II. pathogenesis of CNS involvement:

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