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

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. 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

32. 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

33. II. pathogenesis of CNS involvement:

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