Dr Abdul Ghaffar

VIDEO LECTURE

 IMMUNOLOGY - CHAPTER   NINETEEN 

  IMMUNODEFICIENCY 

TEACHING OBJECTIVES

Know the primary and secondary immunodeficiencies

Know immunodeficiencies in AIDS and other conditions

Know the major primary immunodeficiencies and their features

Understand the relationship between site of lesion and resulting immunodeficiency

Know the diagnostic tests for different immunodeficiencies

SECONDARY AND IATROGENIC IMMUNODEFICIENCIES 

Bacterial, viral, protozoan, helminthic and fungal infections may lead to B cell, T cell, PMN and macrophage deficiencies. Most prominent among these is acquired immunodeficiency syndrome (AIDS). Secondary immunodeficiencies are also seen in malignancies.

Cellular abnormalities of lymphocytes: There is a decrease in the number of helper-inducer (CD4) T cells, and consequently a reversal in CD4⁺/CD8⁺ T cell ratio. Natural killer cell number is within normal range but their activity is reduced.

Functional abnormalities seen in vivo: AIDS patients have an increased susceptibility to infections with opportunistic organisms (Pneumocystis carinii, Toxoplasma gondii, Cryptococcus neoformans, herpes simplex, herpes zoster, cytomegalovirus, Mycobacterium avium-intracellular, etc). These patients also have increased incidence of neoplasms (Kaposi's sarcoma). Delayed hypersensitivity response to common antigens (tetanus, diphtheria, streptococcal antigen, tuberculin, Candida antigen, trichophyton, etc.) is decreased in AIDS patients. They fail to produce antibody in response to various antigenic challenges (KLH, tetanus toxoid, pneumococcal polysaccharide).

 These include a progressive decrease in thymic cortex, hypo-cellularity of and reduction in the size of thymus, a decrease in suppressor cell function and hence an increase in auto-reactivity, a decrease in CD4 cells functions. By contrast B cells functions may be somewhat elevated.

B cell deficiencies have been noted in multiple myeloma, Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia and well differentiated lymphomas. Hodgkin's disease and advanced solid tumors are associated with impaired T-cell functions. Most chemotherapeutic agents used for treatment of malignancies are also immunosuppressive.

Other conditions in which secondary immunodeficiencies occur are sickle cell anemia, diabetes mellitus, protein calorie malnutrition, burns, alcoholic cirrhosis, rheumatoid arthritis, renal malfunction, etc.

WEB RESOURCES

When the Body's Defenses are Missing--Primary Immunodeficiency 
Booklet from National Inst of Child Health and Human Development

WEB RESOURCES

The 10 Warning Signs of Primary
Immunodeficiency Diseases (NIAID)

Primary immunodeficiencies are inherited defects of the immune system (figure 1). These defects may be in the specific or nonspecific immune mechanisms. They are classified on the basis of the site of lesion in the developmental or differentiation pathway of the immune system.

Individuals with immunodeficiencies are susceptible to a variety of infections and the type of infection depends on the nature of immunodeficiency (Table 1).

There are variety of immunodeficiencies which result from defects in stem cells differentiation and may involve T-cells, B-cells, and/or immunoglobulins of different classes and subclasses (Table 2).

Reticular dysgenesis is a very rare (4 reported cases) but fatal disease, characterized by absence or severe deficiency of lymphocytes and granulocytes although erythrocytes and platelets are normal.

Severe combined Immunodeficiency: These are known as severe combined immunodeficiencies (SCID). In about 50% of SCID patients the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal. They are both characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes. Thymic shadows are absent on X-rays. Patients with SCID are susceptible to a variety of bacterial, viral, mycotic and protozoan infections.

The x-linked severe SCID is due to a defect in gamma-chain of IL-2 also shared by IL-4, -7, -11 and 15, all involved in lymphocyte proliferation and/or differentiation. The autosomal SCIDs arise primarily from defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP, respectively, and cause toxicity to lymphoid stem cells. Other genetic defects leading to SCID include those for RAG1, RAG2 and IL7-alpha. If suspected of SCID, the patient must not receive live vaccine, as it will result in progressing disease.

Diagnosis is based on enumeration of T and B cells and immunoglobulin measurement. Severe combined immunodeficiency can be treated with bone marrow transplant (see MHC and transplantation. Recently, autosomal SCID patients with ADA deficiency have been treated with a retroviral vector transfected with the gene with some success.

WEB RESOURCES

NLM - DiGeorge Syndrome 
OMIM - DiGeorge Syndrome 
NCBI - DiGeorge Syndrome 
 

DiGeorge's syndrome: This the most clearly defined T-cell immunodeficiency and is also known as congenital thymic aplasia/hypoplasia, or immunodeficiency with hypoparathyroidism. The syndrome is associated with hypoparathyroidism, congenital heart disease, low set notched ears and fish shaped mouth. These defects results from abnormal development of fetus during 6th-10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed. No genetic predisposition is clear and not all DiGeorge syndrome babies have thymic aplasia. A thymic graft taken from an early fetus (13-14 weeks of gestation) can be used for treatment. Older grafts may result in GVH reaction. In severely immunodeficient DiGeorge patients, live vaccines may cause progressive infections. DiGeorge syndrome is caused by a deletion in chromosome 22. The deletions are of variable size but size does not correlate with severity of disease. In about 6% of cases, the chromosome 22 microdeletion is inherited but most cases result from de novo deletion which may be caused by environmental factors.

CASE PRESENTATION

Pediatric Pathology
DiGeorge Syndrome
A 24-day-old Term Infant with Seizures
(Department of Pathology, University of Pittsburgh)

Ataxia-telangiectasia: This is a deficiency of T cells associated with a lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area (telangiectasis). T-cells and their functions are reduced to various degrees. B cell numbers and IgM concentrations are normal to low. IgG is often reduced and IgA is considerably reduced (in 70% of the cases). There is a high incidence of malignancy, particularly leukemias, in these patients. The defects arise from a breakage in chromosome 14 at the site of TCR and Ig heavy chain genes.

Wiskott-Aldrich syndrome: This syndrome is associated with normal T cell numbers with reduced functions, which get progressively worse. IgM concentrations are reduced but IgG levels are normal. Both IgA and IgE levels are elevated. Boys with this syndrome develop severe eczema, petechia (due to platelet defect and thrombocytopenia). They respond poorly to polysaccharide antigens and are prone to pyogenic infection. These patients have a defective WASP protein which is involved in cytoskeletal reorganization.

MHC deficiency (Bare leukocyte syndrome): A number of cases have been described in which there is a defect in the MHC class II transactivator (CIITA) protein gene, which results in a lack of class-II MHC molecule on their APC. Since the positive selection of CD4 cells in the thymus depends on the presence of this MHC molecules, these patients have fewer CD4 cells and are infection prone. There are also individuals who have a defect in their transport associated protein (TAP) gene and hence do not express the class-I MHC molecules and consequently are deficient in CD8⁺ T cells.

There are a number of diseases in which T cell numbers and functions are normal: B cell numbers may be low or normal but immunoglobulin levels are low. These are briefly summarized below.

x-linked infantile hypogammaglobulinemia: x-linked hypogammaglobulinemia, also referred to as Bruton's hypoglobulinemia or agammaglobulinemia, is the most severe hypogammaglobulinemia in which B cell numbers and all immunoglobulin levels are very low. The patients have failure of B-cell maturation associated with a defective B cell tyrosine kinase (btk) gene. Diagnosis is based on enumeration of B cells and immunoglobulin measurement.

Transient hypogammaglobulinemia: Children, at birth, have IgG levels comparable to that of the mother. The half life of IgG being 30 days, its level gradually decline, but by three months of age normal infants begin to synthesize their own IgG. In some infants, however, IgG synthesis may not begin until they are 2-3 years old. This delay has been attributed to poor T cell help. This results in a transient deficiency of IgG which can be treated with gamma-globulin treatment.

Common variable hypogammaglobulinemia: These individuals have acquired deficiencies of IgG and IgA in the 2nd or 3rd decade of their life and are susceptible to a variety of pyogenic bacteria and intestinal protozoa. They should be treated with specially prepared γ-globulin for intravenous use.  

IgA deficiency: IgA deficiency is the commonest of all immunodeficiencies (1/700 of all Caucasians). About 20% of individuals with IgA deficiency also have low IgG. IgA deficient patients are very susceptible to gastrointestinal, eye and nasopharyngeal infections. Patients with IgA deficiency have a high incidence of autoimmune diseases (particularly immune complex type) and lymphoid malignancies. Anti-IgA antibodies (IgG) are detected in 30 to 40 percent of patients who should not be treated with γ-globulins. Laboratory diagnosis is based on IgA measurement.

Selective IgG deficiency: Deficiencies of different IgG subclasses have been found. These patients are susceptible to pyogenic infections. 

Hyper-IgM immunodeficiency: Individuals with this type of immunodeficiency have low IgA and IgG concentrations with abnormally high levels of IgM. These patients cannot make a switch from IgM to other classes which is attributed to a defect in CD40L on their CD4 cells. They are very susceptible to pyogenic infection and should be treated with intravenous γ-globulins.

Primary immunodeficiencies of the nonspecific immune system include defects in phagocytic and NK cells and the complement system

Defects of the phagocytic system

Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a variety of infections.

Cyclic neutropenia: It is marked by low numbers of circulating neutrophil approximately every three weeks. The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production.

Chronic granulomatous disease (CGD): CGD is characterized by marked lymphadenopathy, hepato- splenomegaly and chronic draining lymph nodes. Leukocytes have poor intracellular killing (figure 2) and low respiratory burst. In majority of these patients, the deficiency is due to a defect in NADPH oxidase (cytochrome b₅₅₈ : gp91^phox, or rarely gp22^phox) or other cofactor proteins (gp47^phox, gp67^phox) that participate in phagocytic respiratory burst. These patients can be diagnosed on the basis or poor Nitroblue tetrazolium (NBT) reduction which is a measure of respiratory burst. Interferon-γ therapy has been successful.

Leukocyte Adhesion Deficiency: Leukocytes lack the complement receptor CR3 due to a defect in CD11 or CD18 peptides and consequently they cannot respond to C3b opsonin. Alternatively there may a defect in integrin molecules, LFA-1 or mac-1 arising from defective CD11a or CD11b peptides, respectively. These molecules are involved in diapedesis and hence defective neutrophils cannot respond effectively to chemotactic signals. 

This syndrome is marked by reduced (slower rate) intracellular killing and chemotactic movement accompanied by inability of phagosome and lysosome fusion and proteinase deficiency. Respiratory burst is normal. Accompanying NK cell defect and platelet and neurological disorders are noted.

Complement abnormalities also lead to increased susceptibility to infections. There are genetic deficiencies of various components of complement system, which lead to increased infections. The most serious among these is the C3 deficiency which may arise from low C3 synthesis or deficiency in factor I or factor H. 

1. Reticular dysgenesis
2. Cyclic neutropenia
3. Chronic granulomatous disease
4. Severe combined immunodeficiency
5. DiGeorge Syndrome
6. Abnormal T cell functions
7. x-linked infantile (Bruton's) hypogammaglobulinemia
8. Selective immunoglobulin deficiencies
9. Hyper IgM immunodeficiency

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