Lecture 25 - Immunodeficiency

IMMUNODEFICIENCY DISEASES (IDD)

Definition: A disease that is the result of loss of function (or defective function) of a component of the immune system. It can be due to the absence of that component. Types: 1o

- inherent, congenital (Intrinsic defect in a cell)

2o

- acquired (Extrinsic factors e.g. radiation, drugs)

Clues: Recurrence of serious infections starting early after birth caused by: i. Encapsulated bacteria, e.g. streptococci, staphylococci, H. influenzae due to defect in C, phagocytes, Ab ii. Viruses, fungi or intracellular bacteria due to defect in CMI

PRIMARY IDD Defects associated with components of innate or adaptive immunity I. B cells .VI II. T cells.VIII III. Macrophages .X IV. Complement.XII

I. B cell deficiency 

The most common ID diseases

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Wide range of defects: complete absence of B cells, AFC or only absence of Ab

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Patients suffer from mainly encapsulated bacterial infections (not fungal or viral since CMI is normal)

Types:

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X-linked agammaglobulinemia (Bruton’s agammaglobulinemia)

 Common in male infants  Immune defect: absence of mature B cells in lymphoid tissue and blood, no tonsils, small lymph nodes, low or no serum Ig

 Intact CMI

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Specific abnormality: blockage in maturation of pre-B cells to B cells in BM

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Infants protected up to 6 months, then manifest recurrent bacterial

infections

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Treatment: life-long periodic gamma-globulin injections

2. Common variable hypo-gammaglobulinemia  Affect both sexes, adults (late onset, 15-35 yrs), familial incidence but no definite genetic basis  Immune defect: low serum Ig, low plasma cell level, Abnormal function of B cells but normal no. of B cells in blood  Specific abnormality: defective differentiation of B cells into plasma cells  Acquired [e.g. viral infection (EBV)]  Treatment: periodic gamma-globulin injections

II. T cell deficiency  defects in CMI lead to defects in HMI  Defects in CMI lead to opportunistic infections (viruses, fungi, parasites, intracellular bact.), live vaccines (e.g. measls)  Several Types:

MHC class II deficiency .1  Immune defect: No CD4+ mature T cells, no functional APC leads to reduced activation of B cells & Tc cell, no Ab  Specific abnormality: genetic defect in class II expression on MQ, B cells  Death by 5 yrs due to bacterial & viral infections

2. Severe Combined Immunodeficiency (SCID)  Immune defect: low count of T & B cells  Specific abnormality: defect in lymphoid stem cell differentiation or defect in developmental pathways in thymus & bone marrow  Most severe form, associated with recurrent fatal infections early in life,

prolonged diarrhea (Rota virus), pneumonia (pneumocystis), Bacterial GIT infections, infection/death after immunization with attenuated live vaccines e.g. BCG Treatment: bone marrow transplantation (or die within 2 yrs), (gene therapy)

DETECTION B cell defects 

Measurement of level of serum Ig

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Enumeration of peripheral B cells

T cell defects 

Enumeration of peripheral T cells and T cell subpopulations

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T cell proliferation tests

III- Complement deficiency Defect in: C1- C9 components can result in defective opsonisation of bacteria, recurrent infections by Neisseria spp., immune complex diseases (e.g. SLE-like)

IV- Defects in phagocytes

Defects associated with myeloid cells (monocyte/MQ lineage, neutrophils)

Leukocyte adhesion deficiency .1 

Immune defect: Adherence defect in leukocyte

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Specific abnormality: Defective Adhesion molecules Consequences:

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Failure of inflammatory cells to migrate Defective Phagocytosis of opsonised bacteria Defective T cell help in B cell activation Defective CTL killing

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 

Lazy leukocyte syndrome .2 Immune defect: defective neutrophil chemotaxis

3. Chronic granulomatous disease (CGD)

Immune defect: defective killing of intracellular bacteria by phagocytes

Specific abnormality: Phagocytes fail to produce Oxygen intermediates (O2-, H2O2)

Associated with recurrent bacterial & fungal infections, disseminated granulomas, children die of septicemia by 7 years of age Treatment: Antibiotics Bone marrow transplantation

SECONDARY IDD Due to extrinsic, environmental factors: 1 . Therapeutic drugs (post-transplant immuno-suppression, cancer chemotherapy) 2. Protein malnutrition, aging 3. Chronic conditions (e.g. diabetes) 4. Burns leads to severe loss of Ig via damaged skin 5. Infections (e.g. HIV)

(Acquired Immunodeficiency Disease (AIDS

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Causative agent: HIV

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Target cells: CD4+ T cells, monocytes, macrophages, dendritic cells, etc.

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Importance of gp120

Disease is in several stages: 1. Asymptomatic for years (latency)

2. AIDS with fever, wt loss, major opportunistic infections when no. of CD4+ is low, malignancies

cells

Cellular defects in HIV infection cells

Abnormality

T cells

Low CD4+ count Defective function

APC

Reduced IL-1 & TNF production

B cells NK cells

Polyclonal activation Defective killing

Main effects Lo cell proliferation Lo cytokine release Lo Tc activity Lo Ag presentation Lo MHC-II expression Lo Chemotaxis Lo Killing Hi Ig production

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Diagnosis: detection of viral Ag, anti-viral Ab

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Prognosis: CD4/CD8 ratio, skin tests (DTH), Lymphocyte transformation test

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Treatment: 1. Treatment of microbial infections 2. Anti-viral drugs 3. Immunorestoration: BM transplantation, Ig injections, cytokines