IMMUNOPATHOLOGY II: IMMUNODEFICIENCY DISORDERS

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I. INTRODUCTION

• Why study the immunodeficiency diseases?
• General approach to diagnosis and therapy

II. CLASSIFICATION, PATHOPHYSIOLOGY, AND THERAPY OF IMMUNODEFICIENCY DISORDERS

• Primary Immunodeficiencies
  
  • B cell deficiencies
    • Selective (e.g. IgA deficiency)
    • Nonselective (e.g. Bruton's X-linked agammaglobulinemia)
  • T cell deficiencies (e.g. DiGeorge's syndrome)
  • Combined deficiencies (e.g. severe combined immune deficiency disease)
  • Other
    • Complement deficiencies
    • Disorders of phagocytic cells (e.g. chronic granulomatous disease of childhood)
      
      
• Secondary (acquired) Immunodeficiencies
  
  
• Evaluation of Patients with Suspected Immunodeficiencies
  
  
  • History
    • Types of infections - location, frequency, and response to therapy
    • Immunizations, especially live virus vaccines
    • Family history
    • Social and sexual history
  • Physical Examination
    • Evaluation of lymphoid tissue
    • Growth abnormalities
    • Other congenital abnormalities
    • Infections

    
    

  • Laboratory Evaluation
    • B cell immunity
      • Quantitative immunoglobulins - IgG, IgM, IgA
      • Specific antibodies - anti-tetanus, polio virus, rubella, isohemagglutinins (anti-A, anti-B)
    • T cell immunity
      • White blood cell count and differential count (% lymphocytes)
      • T cell enumeration and T cell subsets (T helper and T suppressor cells)
      • Skin tests for delayed hypersensitivity (PPD, mumps antigen, Candida antigen, etc.)
    • Other
      • WBC count and differential (% neutrophils and monocytes)
      • Serum complement levels
        
        
• Therapeutic Approaches to Reconstitution
  
  
  • Immunoglobulin Replacement
  • Thymus Transplants
  • Bone Marrow Transplants
    
    
• SCIDS as a Prototype Immune Deficiency Disorder
  
  
  • Background
    • Frequency
    • Inheritance patterns
    • Age distribution
  • Clinical Features
    • Age of onset
    • Infectious complications
    • Graft vs. host disease
    • Immunization with live virus vaccines
    • Associated problems
  • Laboratory Tests
    • Total lymphocyte count
    • Lymphocyte subsets
    • Immunoglobulin levels
    • Additional laboratory data
  • Pathogenesis of SCIDS
  • Therapy and Clinical Course
    • Bone marrow transplantation
    • Gene therapy for A.D.A. deficiency

KEY CONCEPTS:

1. Immunodeficiency diseases can be classified according to the "arms" or compartments of the immune system that are affected.
2. The types of infections observed in immunodeficient patients provide strong evidence for the nature of the immune defect.
3. The evaluation of patients for immunodeficiency disorders requires a systematic evaluation of the patient's history, physical examination, and laboratory findings.
4. Therapeutic approaches have been developed that reconstitute the immune system based on the nature of the underlying defect.

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I. INTRODUCTION

• General Approach to Diagnosis and Therapy
  
  
  • Prior to 1981, discussions about immunodeficiency disorders focused largely on primary immunodeficiencies, experiments of nature that provided unique insight into the function and development of the immune system. These disorders, though rare, are important to consider in the differential diagnosis of children with chronic or recurrent infections. In 1981, the first cases of AIDS were described. Subsequently, several hundred thousand cases of AIDS have been reported worldwide. As a result, the term "immunodeficiency disease" is familiar even to school children. This brief review is intended to provide an overview of primary and secondary immunodeficiency disorders which will serve as a framework for understanding the approach to diagnosis, classification, and therapy of patients with these diseases.
    
    
• Clinical and Diagnostic Features of Immunodeficiency Disorders
  
  
  • In common and with most medical problems, the approach to accurate diagnosis of immunodeficiency disorders begins with the history. Of particular importance is a history of chronic or recurrent infections. Primary immunodeficiencies occur mainly in children, at an age when frequent infections are common even in otherwise healthy individuals. But children with immunodeficiency disorders are different. Their infections tend to be progressive and unremitting. Bacterial infections may respond poorly to appropriate antibiotics. Unusual opportunistic infections may occur. Because they are chronically infected, these children tend to be small for their age ("failure to thrive"). Finally, some of these children may have congenital abnormalities involving other organ systems.
    
    
  • The types of organisms causing infections in these patients provide an important clue to diagnosis. Opportunistic infections (viruses, protozoa, fungi) suggest a defect in the T cell arm of the immune response, whereas infections caused by encapsulated, pyogenic bacteria (pneumococci, meningococci, H. influenzae, group A streptococci) suggest an antibody defect or impairment of nonspecific defense mechanisms which amplify the immune response (disorders of phagocytic cells or complement deficiencies). It is noteworthy, however, that certain viruses may cause unusually severe disease in patients with B cell defects, too. Infections with the hepatitis viruses, enteroviruses, and ECHO viruses are particularly problematic in these patients. Opportunistic neoplasms, especially malignant lymphomas, are observed in several immunodeficiency disorders, often but not always late in the course of the disease. The increased frequency of malignant lymphoma, Kaposi's sarcoma, and other aggressive skin cancers in AIDS patients is an example of this susceptibility.
    
    
  • Finally, exposure to live virus vaccines may be disastrous in some patients with immunodeficiency disorders involving T cell immunity. Over 40 examples of post-vaccination poliomyelitis have been reported in these patients, including one patient from Vermont.
    
    
  • Two additional points regarding the evaluation of patients with immunodeficiency disorders should be made. First, since maternal IgG crosses the placenta, infants with B cell defects tend to present late in the first year of life. Conversely, patients with T cell defects present early in life, usually in the first 3-6 months after birth. Second, non-immune abnormalities must also be considered in the differential diagnosis of children with recurrent infections. For example, anatomical abnormalities should be suspected if the infections occur repeatedly in one specific anatomic site (e.g. pneumonia in the right middle lobe of the lung). Another example is, cystic fibrosis, a common genetic defect of chloride ion transport. The transport defect results in the formation of thick, tenacious mucus, which obstructs small bronchi in the lungs and promotes the development of pneumonia. This disease is a fairly common cause of recurrent pneumonia in children. In contrast in patients with immunodeficiency disorders the infections tend to be generalized and involve many different organ systems.
    
    
  • Physical examination is helpful to assess the site and nature of the infections, identify other, associated congenital abnormalities, evaluate growth status, and to examine the status of lymphoid tissue in various locations. Patients with T cell defects will often lack identifiable lymphoid tissue such as lymph nodes, tonsils, and adenoids even at sites draining active infections. Similarly, chest X-rays may reveal the lack of a thymus shadow. Paradoxically, in some B cell abnormalities involving the failure of terminal differentiation to plasma cells, marked lymphoid hyperplasia in lymph nodes and in gut-associated lymphoid tissue may be observed.
    
    
• Laboratory Evaluation of Patients with Suspected Immunodeficiency Disorders
  
  
  • The selective use of diagnostic tests provides a cost-effective approach to the evaluation of patients with suspected immunodeficiency disorders. Table 1 succinctly summarizes some of the tests that are useful in various clinical circumstances. In children with recurrent pneumonia a sweat chloride test for cystic fibrosis is indicated prior to further laboratory evaluation, since this disorder is relatively common. Also, an erythrocyte sedimentation rate (measures acute phase proteins) has been recommended by some for screening purposes. A normal E.S.R. virtually rules out chronic bacterial infections. Quantitative measurements of serum-immunoglobulins G,M, and A are inexpensive and useful to evaluate the integrity of the B cell arm of the immune response. Since isohemagglutinins against blood group A and B antigens are formed early in life, their detection is useful to assess specific IgM antibodies against polysaccharides antigens.
    
    
  • To screen for T cell defects a white blood cell count, differential count, and morphological evaluation of the peripheral blood smear provides important, useful information. Since T cells normally comprise about 75% of all circulating lymphocytes, lymphocyte counts are usually low in patients with severe T cell defects. Absolute lymphocyte counts below 1500/cu.mm. in adults and 4000/cu.mm. in children less than 1 year of age are abnormal. Another inexpensive and informative method to evaluate T cell defects is to perform skin tests for delayed cutaneous hypersensitivity. For example, diluted candida antigen (available commercially) is injected intradermally, then the area of erythema and induration in the skin is measured 24-72 hours later. A pink lump in the skin greater than 1 cm in diameter is considered a positive response. Unfortunately skin tests are most helpful in older children and less so in preschoolers.
    
    
  • If screening tests are abnormal or if the history strongly suggests an immune deficiency more sophisticated (and more expensive) tests can be ordered. For example, specific antibodies against diphtheria, tetanus, polio virus, and pneumococcal polysaccharides, and H. influenza can be measured after immunization. To illustrate the utility of these tests, patients with AIDS and AIDS-related complex are often hypergammaglobulinemic, but form specific antibodies poorly.

• Furthermore, it is possible to enumerate B cells, T cells, natural killer cells and their subsets using flow cytometry. A list of monoclonal antibodies available in our laboratory for this purpose is given in Table 2. T cell defects in particular may be detected using lymphocyte stimulation by plant lectins (phytohemagglutinin, concanavalin A, pokeweed mitogen), allogeneic cells, or specific antigens (tetanus toxoid, candida antigen). These tests are very expensive and should be reserved for highly selected cases.
  
  
• A full discussion of phagocyte disorders and complement deficiencies is beyond the scope of this essay. Suffice it to say, tests to evaluate leukocyte numbers, functions, and cell surface characteristics are available in the laboratory. Similarly, the measurement of total hemolytic complement (CH50) and individual complement components is available in our own laboratory or in reference laboratories.

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II. CLASSIFICATION, PATHOPHYSIOLOGY, AND THERAPY OF IMMUNODEFICIENCY DISORDERS

The classification of the immunodeficiency disorders can be best understood by considering the normal development of the immune system and the cell collaborations necessary to generate an effective immune response. Lymphocytes are derived from hematopoietic stem cells that reside in the fetal liver and bone marrow. These cells proceed through an orderly sequence of maturation even in the absence of foreign antigens. Early in differentiation gene rearrangements occur which commit the cell to either T cell or B cell differentiation. Further development of T cells occurs in the thymus gland, whereas B cell development occurs in the bone marrow. At each step in the differentiation process a particular set of cell surface characteristics is expressed which can be readily identified by flow cytometry. Since some of the immunodeficiencies4P¿5:¦ed by matura2) arrest during differentiation, characterization of cell surface markers can be diagnostically useful. Parenthetically, this approach to diagnosis is also valuable in the evaluation of lymphocytic leukemias and malignant lymphomas.

Once functionally mature cells have developed, the generation of a normal immune response depends upon collaboration between antigen-presenting cells (A.P.C.), T helper cells, and T, B, and NK effector cells. These interactions are tightly regulated by specific and nonspecific regulatory cells. Products (cytokines) released from these cells modulate the immune response. A partial list of important cytokines is given in Table 3. It is also important to note that cell-cell interactions depend upon the participation of cell surface molecules including the T cell receptor and surface immunoglobulin, antigen-binding proteins (HLA class I and II antigens), and adhesion molecules (LFA-1, LFA-3, ICAM-1) and their ligands which promote efficient binding between cells. Signal transduction from the cell surface to the interior is essential to promote cell proliferation and differentiation. Effector molecules (cytokines; antibodies) amplify the immune response by virtue of their proinflammatory activities. Complement activation by antigen antibody complexes is a specific example of an important amplification mechanism.

Impairment of normal immunity may result from defects at any stage of cell differentiation, collaboration, or amplification, whether hereditary or acquired. Table 4 lists some selected examples of immune deficiency disorders and the point in cell differentiation at which the defect responsible for the abnormality occurs. This list is not comprehensive by any means. More complete information about specific disorders can be found in your text book and in the references.

TABLE 2: Cell Surface Characteristics of Lymphoid Cells*

	T CELLS		B CELLS		NK CELLS
CD2	precursor T cells	CD19	precursor B cells	CD56	mature NK cells
CD5	precursor T cells	CD20	precursor B cells	CD16	mature NK cells
CD7	precursor T cells	Ia	precursor B cells
CD3	mature T cells	SmIg	mature B cells
CD4	T helper/inducer cells	CD22	mature B cells
CD8	T cytotoxic/suppressor cells	CD38	plasma cells

*CD stands for cluster of differentiation, referring to a method used to compare monoclonal antibodies reacting with a similar or identical epitope.

TABLE 3: Selective Cytokines that Modulate the Immune Response

	ORIGIN	ACTION
IL-1	Macrophages	Primes T cells; pyrogen
IL-2	T cells	Stimulates proliferation of T, B, and NK cells
IL-4	T cells	Governs B cell isotope switch to IgG production
IL-6	Macrophages; T cells	Promostes B cell differentiation
TNF-alpha	Macrophages	Proinflammatory; activates macrophages and endothelial cells
Interferon-gamma	T cells	Activates macrophages; up-regulates HLA class I and II antigen system

TABLE 4: Selected Immunodeficiency Disorders

Primary Immunodeficiency Disorders
DISORDER	DEFICIENCY	DEFECT	PRESENTATION
X-linked agamma globulinemia	Antibody	Pre B cell	Pyogenic infections in children
Selective IgA deficiency	IgA antibody	Terminal differentiation of IgA B cells	Recurrent respiratory and G.I. infections
Common, variable immunodeficiency	Antibody	Terminal differentiation of all B cells	Bacterial infections in adolescents and young adults; lymphoma a late complication
DiGeorge's syndrome	T cells	Dysmorphogenesis of 3rd and 4th pharygeal pouch (thymus)	Tetany, congenital heart defects, opportunistic infections, post- transfusion GVHD; post-vaccination infection
Severe combines immuno-deficiency disease (SCID)	Antibody T cell	Various Stem cell defects, occasionally adenosine deaminase deficiency	Opportunistic infections in infants 3 6 months old; GVHD; post-vaccination infections
Acquired Immunodeficiency Disorders
AIDS	T helper cell deficiency	HIV mediated destructions of CD4+ cells	Opportunistic infections and neoplasms
Chronic lymphocytic leukemia	Antibody	Unknown	Pyogenic infections, especially pneumococci

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Several of the genetic abnormalities responsible for the primary immunodeficiency disorders have been identified and are described in the references. For example, the molecular defect in X-linked SCID has been mapped to the 913 locus of the X-chromosome. Mutations in this region result in the formation of a defective 1L2-R gamma chain, a molecule essential for the normal differentiation of T and B lymphocytes.

Alternatives for therapy can also be deduced from an understanding of the nature of the defect causing the immunodeficiency. For example, patients with X-linked agammaglobulinemia, a pan B cell defect, can be treated with immunoglobulin replacement therapy. Intravenous IgG from a pool of healthy donors is available for this purpose (but is very expensive!) Similarly, if the primary defect is failure to produce lymphoid stem cells (severe combined immunodeficiency disease, SCID), then bone marrow transplantation to replenish progenitor-cells is a logical therapeutic choice. Successful transplantation has been reported in 60% - 80% of these infants. As new genetic information pinpoints the specific defects leading to immunodeficiency disorders, gene therapy to correct these defects may be possible and has been attempted. In fact, in A.D.A. deficiency. In contrast, bone marrow transplantation has been unsuccessful in AIDS, since eradication of the HIV virus is not yet possible.


REFERENCES

Buckley RH. Immunodeficiency Diseases. JAMA. 268:2797, 1992.

Greenberg P. Immunopathogenesis of HIV-infection. Hosp. Practice 27(2):109, 1992.

Huston DP,et al.Immunoglobulin deficiency syndromes and therapy. J Allergy Clin Immunology. 87:1-17, 1991.

Parkman R.The biology of bone marrow transplantation for SCID. Adv. Immunol 49:381,1991.

Rosen FS; Cooper MD; Wedgwood RJP. The primary immunodeficiencies. NEJM 333:431, 1995.

Voss SD; Hong R; Sondel PM. Severe combined immunodeficiency, Interleukin-2 (IL-2), and the IL-2 Receptor: Experiments of nature continue to point the way. Blood 83:626, 1994.

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