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