lecture 4. primary immune deficiency diseases. lymphocyte development and sites of block in primary...
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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 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 malignancyChronic renal failure Side effects of immune suppression
,irradiation ,or chemotherapy for cancer or other autoimmune diseases .
( 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. 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. 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
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
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
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
THE MULTIPLE EFFECTS OF CD4+CELL AFTER HIV INFECTION:
HIV
CD4
CD4 CD8 B-cellNK Macrophage
*↓ResponseTo solublea.g.*↓Cytokinesecretion
↓Specificcytotoxicity
↓Killing of Tumour cells
↓ IgProduction to new a.g.
*↓ CytotoxicAbility*↓chemotaxis*↓IL-1 secretion*poor a.g. presentation
II. pathogenesis of CNS involvement:
HIV
TNF-TNF-αα IL-6IL-6 NONO
microglia
IL-1
KAPOSI SARCOMA
CD4 cell
InfectedB-cell
Cytokines
Proliferation & Angiogenesis
HIV
KSHV(HHV-8)
Mesenchymalcells
tat-protein Kaposi Sarcoma