Hypersensitivity

While reactions between antigens and the immune system are important protective defenses, they also have the potential of injuring normal tissues and producing disease. Disorders that result from uncontrolled, exaggerated, or misdirected immune responses are called hypersensitivity diseases.

Hypersensitivity can involve either humoral or cell-mediated responses.

The antigens that stimulate pathologic immune responses are derived from two main sources:

1. Foreign antigens - Foreign (non-self) antigens - often referred to as allergens - can trigger allergies. Allergens are most commonly derived from chronic infections, or from the environment. Individuals who are genetically pre-disposed to allergic reactions are said to be atopic. Allergic reactions are associated with exaggerated inflammatory responses which injure tissues.

2. Self antigens - Abnormal immune responses directed primarily at antigens within the body are called autoimmunity. Recall that during the maturation of T and B Lymphocytes, those cells with reactivity against self-antigens are normally eliminated or held in check. Autoimmunity represents a failure of the immune system to distinguish between self and non-self - i.e., a breakdown in normal immunologic self tolerance.

Classification and Mechanisms of Hypersensitivity Diseases

In terms of their immunologic mechanisms, allergy and autoimmunity typically follow one of four patterns:

1. TYPE I: IMMEDIATE HYPERSENSITIVITY: Figure 5. This represents one of the most powerful immune responses in the body. It results from the activation of mast cells by IgE antibodies followed by the rapid release of chemical mediators of inflammation. This reaction is called immediate hypersensitivity because it develops within minutes of antigenic stimulation. Only certain antigens are capable of stimulating immediate hypersensitivity reactions. Additionally, atopic individuals tend to produce higher levels of IgE antibodies in response to antigenic stimulation as compared to normal non-atopic individuals and are therefore at greater risk for immediate hypersensitivity.

   The development of immediate hypersensitivity is a two step process:

   1. Sensitization phase - When the immune system of atopic individuals is first exposed to an allergen, B lymphocytes produce excess IgE antibodies. These antibodies have a strong affinity for mast cells (and basophils) and coat the surface of these cells by binding to receptors for the heavy chain portion of the IgE molecule (IgE Fc Receptors).

   2. Activation phase - Later when sensitized mast cells, coated with IgE antibodies, are re-exposed to the allergen, they rapidly release vasoactive mediators such as histamine and serotonin from cytoplasmic granules. A requirement for activation of mast cells appears to be the cross-linking of surface IgE molecules by the inciting allergen. Later, prostaglandins and leukotrienes are also synthesized from the mast cell plasma membrane. Among other things, this leads to the accumulation of neutrophils and eosinophils at the site of antigenic stimulation.. This stage of the immediate hypersensitivity reaction is sometimes referred to as a late phase response.

   The clinical manifestations of immediate sensitivity reactions depend on whether the antigen in introduced into the skin, lung, or blood stream.

   Immediate Hypersensitivity Reactions in the Skin and Mucous Membranes: (urticaria, angioedema, allergic rhinitis)

   • Histamine seems to be the primary mediator of immediate hypersensitivity reactions involving the skin and mucous membranes. These reactions can be blocked by the administration of anti-histamines.

   • Histamine causes dilation of capillary venules which results in increased blood flow to the skin (redness and warmth) with the extravasation of plasma into the interstitial spaces (wheal). Immediate hypersensitivity reactions involving mucous membranes of the nose and throat produce swelling, and increased mucus secretions.

   • Degranulation of mast cells also releases substances which are chemotactic for eosinophils and other WBC's. For this reason, increased numbers of eosinophils are typically found in the blood, or at the site of allergic reaction.

   • The late phase response in the skin seems to be one mechanism for producing certain forms of eczema. This reaction is not blocked by antihistamines.

   Immediate Hypersensitivity Reactions in the Lung:

   • Immediate hypersensitivity reactions to inhaled allergens can lead to bronchospasm and some forms of asthma.

   • Histamine does not produce significant bronchospasm. Instead, it is the late phase mediators prostaglandins and leukotrienes that are responsible for the intense bronchospasm and increased mucous secretion of immediate hypersensitivity reactions in the lung.

   • Because histamine does not contribute to bronchospasm, anti-histamines are not effective in treating bronchospasm. Other drugs such as epinephrine and theophylline which relax bronchial smooth muscle - or drugs such as cromolyn and corticosteroids which block mast cell degranulation - are more effective.

   • Not all asthma is allergic or IgE mediated. In some people the smooth muscle cells lining the airways are "hyper-reactive" and constrict in response to non-immunologic stimuli. However, even in these cases, some inflammation can be demonstrated.

   Systemic Hypersensitivity (Anaphylaxis):

   • Massive release of mast cell vasoactive mediators produce loss of vascular tone (vasodilation) throughout the body with a fall in blood pressure, decreased tissue perfusion, and shock. Urticaria, bronchospasm, laryngeal edema, vomiting, and diarrhea also occur.

   • These potentially life-threatening reactions usually result from systemic administration of an allergen (insect sting, injection of certain drugs or serum products, or absorption of allergen across a mucosal surface).

   • Emergency treatment involves administering epinephrine which reverses vasodilation, improves cardiac output, and relaxes bronchospasm. Antihistamines and corticosteroids are also beneficial (but not as the first-line treatment).

   Allergy Desensitization:

   • Frequent, repeated intradermal injections of increasing amounts of an allergen may produce tolerance to it.

   • The immunologic mechanism of desensitization appears to be the development of specific IgG antibodies to the allergen. These IgG antibodies bind with the allergen as soon as it enters the body preventing it from reacting with the IgE antibodies on the surface of mast cells. The IgG coated allergens are then cleared by macrophages.

   • Unfortunately desensitization does not completely eliminate immediate hypersensitivity reactions. At best, they reduce symptoms. The duration of effects are variable. Further, life-threatening anaphylaxis has been known to occur from desensitization therapy itself!

   Non-IgE mediated "Allergy": There are a number of substances which can directly activate mast cells in the absence of IgE and produce so called anaphylactoid (anaphylaxis-like) reactions. They include morphine, shellfish, iodinated radiocontrast agents, certain berries, and aspirin. Anaphylactoid reactions have the same clinical significance as IgE mediated anaphylaxis. They are also managed the same way.

   
   

2. TYPE II: ANTIBODY-MEDIATED (CYTOTOXIC) HYPERSENSITIVITY: Figure 6. This form of hypersensitivity is mediated by IgG or IgM antibodies directed against antigens on the surface of somatic cells or against connective tissue proteins. The antigenic target may be an integral part of the cell membrane, or it may be a substance (e.g., drug) that has been adsorbed onto cell membranes.

   Three mechanisms of antibody mediated cell injury in Type II Hypersensitivity are recognized: complement activation, antibody-dependent cell-mediated cytotoxicity, and anti-receptor antibodies.

   1. Complement Activation - When IgG or IgM antibodies bind to the surface of a cell, complement may be activated leading to the formation of membrane attack complexes that lyse the cell. Activation of complement (C5a and C5b) also attracts inflammatory cells such as neutrophils and macrophages to the antibody-coated cells causing them to be phagocytosed. If the cell or connective tissue structure is too large to be phagocytosed, macrophages and neutrophils may deposit their hydrolytic enzymes and oxidants at the site of antibody binding and produce tissue injury.

      Examples of Type II hypersensitivity associated with complement activation include:

      • Blood transfusion reactions in which incompatible donor RBC's are destroyed by anti-RBC antibodies produced by the recipient.

      • Hemolytic disease of the newborn (erythroblastosis fetalis). Rh negative mothers may develop anti-Rh antibodies after the birth of an Rh positive child. Subsequent Rh positive fetuses will be exposed to the IgG anti-Rh antibodies which cross the placenta and cause destruction of fetal RBC's.

      • Autoimmune hemolytic anemia in which individuals produce antibodies against their own RBC's. These anemias are associated with a positive direct Coombs test.

      • Immune Thrombocytopenic Purpura (ITP) in which individuals produce antibodies against their own platelets. These antibody coated platelets are prematurely removed from the circulation by the spleen producing thrombocytopenia.

      • Drug reactions in which drugs bind with surface proteins on RBC's. The body then develops antibodies against this drug-protein "neoantigen" resulting in lysis of RBC's. (Note that if IgE antibodies are produced against the drug instead of IgG or IgM antibodies, immediate hypersensitivity reactions are likely to occur.)

      • Goodpasture's syndrome is a disease characterized by pulmonary hemorrhages and severe glomerulonephritis. It is caused by an autoantibody directed against a specific type of collagen found in the basement membranes of pulmonary alveoli and glomerular capillaries. Complement activation triggers inflammation which damages pulmonary and glomerular tissues.

      • Acute rheumatic fever is associated with injury to myocardial cells from anti-streptococcal antibodies that cross-react with myocardial proteins. In this case, an antibody against a foreign protein is misdirected against a self protein.

   2. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) - Lysis of antibody-coated cells by granulocytes, natural killer cells, or macrophages. Complement activation not involved.
      • This seems to be the underlying mechanism for Hashimoto's autoimmune thyroiditis (a common cause of HYPOthyroidism). Detection of antithyroid antibodies in the serum is useful diagnostically.

      • ADCC may contribute to some cases of organ transplant and tissue graft rejection.

   3. Anti-Receptor Antibodies - The binding of antibodies to physiologically important cell surface receptors or molecules can inappropriately activate or impair the normal functions of certain cells. This occurs without complement activation or inflammation. Examples include:

      • Myasthenia gravis - Autoantibodies directed against acetylcholine receptors on muscle cells interfere with neurotransmission by motor nerves and cause muscle weakness.

      • Graves disease - Autoantibodies directed against the TSH receptors on thyroid cells mimic Thyroid Stimulating Hormone and cause HYPERthyroidism.

      • Insulin-resistant diabetes mellitus - Some diabetics become resistant to treatment with insulin because of the development of autoantibodies against insulin receptors on cells.

      • Pernicious anemia - Autoantibodies directed against intrinsic factor on the gastric mucosa interferes with vitamin B12 absorption.

   
   

3. TYPE III: IMMUNE COMPLEX-MEDIATED HYPERSENSITIVITY: Figure 7. If the immune system is exposed to an excess of soluble antigen over a prolonged period of time, insoluble complexes of antigen and antibody may form in the circulation. If these antigen-antibody complexes are not adequately removed by phagocytic cells in the spleen or other lymphatic tissues, they can be deposited in the walls of blood vessels, in the kidney, skin, or joints. This leads to activation of the complement system and recruitment of inflammatory cells (neutrophils and macrophages) at the site of immune complex deposition.

   The mechanisms of tissue injury in Type III Hypersensitivity are similar to those of Type II Hypersensitivity (see above). The difference is that Type III injury is not the result of direct binding of antibody to a cell, but rather because "innocent bystander" cells get caught in the cross-fire between immune complexes and activated complement and white blood cells. Two types of antigens cause immune complex hypersensitivity diseases: (1) foreign proteins derived from chronic infections or drugs/ foreign protein injected into the circulation, or (2) self proteins that generate inappropriate autoantibodies. If immune complexes are formed in the circulation they can be deposited in many tissues (especially blood vessels) and produce generalized systemic diseases. If immune complex deposition is restricted to particular organs (such as the kidney) or joints, the disease is localized to these structures.

   Examples of Type III hypersensitivity reactions include:

   • Serum Sickness - This is the classic example of immune complex disease. It was first described in individuals receiving diphtheria or tetanus anti-toxin derived from horse serum. Complexes made up of horse proteins and host antibodies against them were deposited in capillaries of the skin, renal glomeruli, and joints leading to complement-mediated inflammation at these sites. Resulting symptoms, 10-14 days after exposure, included fever, rash, arthritis, and occasionally hematuria. Fortunately, serum sickness is now rarely seen because active immunization with diphtheria and tetanus toxoids has reduced the need for animal derived anti-toxins.

   • Post-streptococcal glomerulonephritis - Immune complexes of streptococcal antigen and anti-streptococcal antibodies are deposited in the glomeruli. This leads to inflammation and increased glomerular permeability to proteins and RBC's (proteinuria and hematuria).

   • Systemic Lupus Erythematosus (SLE) - A chronic multisystem disease associated with a wide array of autoantibodies - especially antibodies directed against DNA and other proteins found in the nucleus of cells (Antinuclear Antibodies - ANA). The reason why these autoantibodies develop is unclear. Immune complex deposition in blood vessels and other tissues produces variable clinical manifestations including vasculitis, nephritis, arthritis, skin lesions, CNS symptoms, pericarditis, endocarditis, and anemia.

     Rheumatoid arthritis is thought to result from a similar immunologic mechanism.

   • Polyarteritis nodosa - A disease seen as a late sequel to hepatitis B infection. Immune complexes of Hepatitis B surface antigen and antibodies are deposited in blood vessels leading to vasculitis. Clinical signs and symptoms vary widely but include fevers, leukocytosis, and peripheral neuritis.

   • Farmer's Lung (Pneumoconiosis) - Caused by chronic exposure to moldy hay. Inhalation of allergen results in the formation of antibodies and the deposition of antigen-antibody complexes in the lung. This leads to pneumonitis and pulmonary fibrosis.

   • Arthus Reaction - Immune complex deposition in capillaries of the skin after intracutaneous injection of an antigen can lead to a localized area of edema, hemorrhage and necrosis called an Arthus reaction. Unlike IgE mediated Type I reactions which appear immediately, Arthus reactions develop over a period of 4-10 hours after injection. The most common situation where Arthus reactions occur is during desensitization therapy for allergies.

   
   

4. TYPE IV: T CELL-MEDIATED HYPERSENSITIVITY: Figure 8. T Cells can cause tissue injury if they inappropriately react with self antigens, or if they react to foreign antigens chronically associated with the body's own cells and tissues. Unlike Types I, II, and III hypersensitivity reactions, antibodies are not involved The two patterns of T Cell-mediated injury are:
   1. Delayed Type Hypersensitivity (DTH) reactions mediated by CD4 Helper T Lymphocytes. Injury results from the hydrolytic enzymes and toxic oxidants secreted by macrophages activated by CD4 lymphocytes. Later, chronic inflammation (manifested by granuloma formation) and fibrosis dominates the clinical picture. Examples of DTH include:
      • Tuberculin reaction - The skin reaction seen with intradermal tests for tuberculosis (PPD, TB Tine). Swelling and induration at the site of injection is seen in those individuals who have been exposed to mycobacterium tuberculosis.

      • Contact dermatitis - Poison ivy, some drugs, and occasionally cosmetics can bind to certain cell surface proteins and become the target for CD4 Helper lymphocytes producing local inflammation, fibrosis and edema.

      • Insulin-dependent Diabetes Mellitus - This disorder is thought to represent a DTH reaction directed against the insulin producing Beta cells in the pancreatic islets of Langerhans. The nature of the event triggering the immune response is unknown.

      • Chronic granulomatous diseases - These include mycobacterium tuberculosis infections and sarcoid. Typically involve the lung.

   2. Lysis of cells by CD8 Positive Cytolytic T Lymphocytes or NK cells.
      • CTL mediated Type IV hypersensitivity plays a major role in organ transplant rejection.

      • The myocardial injury seen in viral myocarditis appears to be mediated in part by CTL's.

Autoimmunity

Autoimmunity involves hypersensitivity reactions directed at self antigens which lead to acute and/or chronic inflammation and cell injury. Autoimmune disorders are also often called connective tissue disorders. Examples include:

• Systemic lupus erythematosus (SLE)

• Scleroderma

• Polymyositis-dermatomyositis

• Sjogren's syndrome

  ...and many more.

Autoimmune disorders commonly target blood vessles (vasculitis) thereby affecting the function of multiple organs and producing a wide range of symptoms and clinical presentations. Specific tissues such as the glomeruli of the kidneys and synovium of joints are also frequent targets of autoimmune reactions.

Although the exact mechanisms of many autoimmune diseases are unknown, several immunologic abnormalities have been identified which seem to contribute to autoimmune reactions:

• Molecular mimicry - Cross-reactions between antibodies to foreign antigens and self antigens. These reactions are usually directed at a specific organ or tissue.

• Lymphocyte activation - As noted earlier, during development, lymphocytes capable of reacting against self antigens in the body are normally inactivated. However, several microorganisms have the ability to reactivate these cells later in life leading to autoimmune reactions. This is one explanation for the observation that many autoimmune diseases seem to occur after certain infections.

• Impaired immune regulation - Defects in those mechanisms designed to turn off or suppress immune responses after they have served their intended purpose can cause exaggerated "hyper-responsiveness" of T and B Lymphocytes. For example, activated lymphocytes normally undergo programmed cell death (apoptosis) after they have completed their immunologic work. Defects (mutations) in those proteins that regulate this process could promote survival of activated lymphocytes and lead to exaggerated immune reactions.

• Exposure of sequestered antigens - During development, some tissues are not exposed to the immune system (CNS, spermatozoa, lens of eye, etc.). As a result, those lymphocytes capable of reacting with these tissues are not inactivated or deleted from the immune system. Later in life, if these structures are exposed to the immune system because of injury or infection, autoimmune reactions may result.

There seems to be a genetic predisposition for autoimmune diseases among individuals inheriting certain alleles of the Major Histocompatibility Complex (Human Leukocyte Antigens). For example, ankylosing spondylitis occurs 90 times more frequently among those positive for HLA-B27. The risk of developing insulin dependent diabetes mellitus is much greater in individuals inheriting the HLA alleles DR3 and/or DR4. The exact mechanism for these associations is still unclear. Hormonal and sex influences seem to play a role in autoimmune diseases. For instance, systemic lupus erythematosus (SLE) affects females about ten times more frequently than males.

Immune Deficiencies

Definition: Immunodeficiency refers to defects in one or more components of the immune system impairing the body's ability to defend itself against infection.

Clinical Features of Immunodeficiency - Clinically, immunodeficiency syndromes are associated with increased susceptibility to infection, increased risk for certain cancers, and increased incidence of autoimmune disorders.

1. Increased susceptibility to infections - Recurrent or chronic infection is a common manifestation of immunodeficiency states. The types of infection provide clues as to the specific immunologic defect involved. Defects in humoral immunity tend to be associated with frequent bacterial infections while defects in cell-mediated immunity typically lead to infections by opportunistic organisms or intracellular pathogens such as viruses. Mucocutaneous candidiasis, pneumocyctis pneumonia, and herpes zoster infections are particularly common with T Lymphocyte disorders. Decreased complement levels, or abnormalities in WBC function, are associated with pyogenic infections similar to those seen in disorders of humoral immunity.

   Examples of Infectious Agents in Different Types of Immune Deficiencies
   Pathogen Type	T-Cell Defect	B-Cell Defect	Granulocyte Defect	Complement Defect
   Bacteria	Bacterial Sepsis, mycobacterial infections	Streptococci, Staphylococci, Haemophilus	Staphylococci, Pseudomonas	Neisseria, other pyogenic bacteria
   Viruses	CMV, Epstein-Barr, varicella-zoster, chronic infections from respiratory and gastrointestinal viruses.	Enteroviral encephalitis (echovirus, coxsackievirus)
   Fungi and Parasites	Candida, pneumocystis carinii	Giardiasis	Candida, Nocardia, Aspergillus
   Special Features	Aggressive disease with opportunistic pathogens, failure to clear infections. Disseminated viral infections. Mucocutaneous candidiasis. Pneumocystis pneumonia.	Recurrent sinopulmonary infections, sepsis, chronic meningitis, chronic otitis. Bacterial diarrhea is common.

   
   

2. Increased cancer risk - The genetic defects associated with many primary immunodeficiency disorders can affect DNA synthesis and DNA repair in many cells. This increases susceptibility to mutations that may lead to malignancies. Patients with T Cell immunodeficiencies are particularly at risk for leukemias and lymphomas.

3. Autoimmunity - Some immunodeficiency syndromes are associated with an increased incidence of autoantibody production and autoimmune disease (e.g., SLE, RA, dermatomyositis).

Classification of Immunodeficiency Disorders - Immunodeficiency syndromes are usually divided into two subcategories: primary and secondary immunodeficiency:

1. Primary Immunodeficiency: Inherited defects of the immune system manifested by abnormal functioning of B and/or T Lymphocytes. Most of these conditions are relatively rare and usually come to light because of chronic recurring infections during infancy (age 6 months - 2 years). Examples include:
   • X-linked Agammaglobulinemia (Bruton's disease) - An inherited disease (recessive pattern) affecting males. The disorder is caused by a genetic defect that prevents B Lymphocytes from maturing and developing normally. Affected patients have decreased numbers of B Lymphocytes and decreased levels of serum immunoglobulins (antibodies) in the serum. The clinical picture is characterized by severe, recurrent infections by staphylococci, streptococcus pneumoniae, or haemophilus beginning at six to eight months of age when the infant becomes depleted of maternally derived antibodies. Common sites of infection include meningitis, pharyngitis, otitis media, bronchitis, and pneumonia. Giardia lamblia infections are also common. Most viral and fungal infections are handled normally because T Lymphocytes are not affected. Treatment involves periodic (usually monthly) injections with pooled human immune globulin (IVIG). Affected individuals have a greater than average risk of autoimmune diseases such as SLE, RA, and dermatomyositis later in life.

   • Common Variable Immunodeficiency - This disorder is characterized by the inability of B Lymphocytes to synthesize and secrete IgG - i.e., patients have hypogammaglobulinemia. B lymphocyte numbers are normal but the cells are functionally defective. It is usually diagnosed in late childhood or early adult life. In addition to frequent infections (sinusitis, bronchitis, pneumonia, otitis, giardiasis), this condition is also associated with an increased risk for developing lymphomas and gastrointestinal malignancies. Common variable immunodeficiency is usually treated with intravenous immunoglobulins (IVIG) typically administered every 3-4 weeks.

   • Selective IgA Deficiency - This disorder is a relatively common condition (1 in 500-600 persons of European descent) characterized by variable degrees of reduced IgA levels accompanied by chronic respiratory, urinary tract, and gastrointestinal infections. Bacterial diarrhea is particularly common. Patient's with IgA deficiency have a high incidence of asthma and other atopic conditions. Selective IgA deficiency is closely related to common variable immunodeficiency (described above). Both disorders may be found in the same family. Autoimmune disorders are also common. Because individuals with selective IgA deficiency can develop severe anaphylactic reactions to injected IgA, IVIG is not used in these patients. Instead infections are treated with antibiotics as they occur.

   • DiGeorge Syndrome - A condition characterized by failure of the thymus to develop during the 12th week of gestation leading to reduced numbers of T Lymphocytes and impaired cell-mediated immunity. Serum immunoglobulin levels are usually adequate. Patients lack a defense against viral, mycobacterial, and fungal infections. Fortunately, some affected children regain T cell function by the age of five years. This apparently occurs because non-thymic lymphatic sites develop the ability to assist T Lymphocytes in their maturation at this time. This syndrome is usually diagnosed shortly after birth because of its association with other congenital defects (low set ears, widely spaced eyes, small jaw, fish-shaped mouth, and heart abnormalities such as PDA and septal defects). Parathyroid dysfunction is also common (hypocalcemia, muscle twitching, tetany). Treatment is supportive. Immunization with live vaccines must be avoided.

   • Severe Combined Immunodeficiency Disease (SCID) - A heterogeneous group of conditions all associated with genetic defects in those lymphoid stem cells that are precursors for both T and B Lymphocytes. This causes functional impairment of both humoral and cell-mediated immunity. Infants with SCID are susceptible to recurrent infections by bacteria, viruses (especially CMV and varicella), candida, and pneumocystis carinii. Typical presentations include severe oral candidiasis, severe diaper rashes, and failure to thrive. SCID is often accompanied by severe lymphopenia. Affected infants almost always succumb to opportunistic infection during the first year of life. The only effective therapy is bone marrow transplantation. One form of SCID associated with a deficiency of an enzyme required for DNA synthesis (adenosine deaminase (ADA)) can be managed with ADA infusions. Gene therapy for ADA deficiency is also being investigated. SCID infants should not receive live vaccines. Blood transfusions should also be avoided.

   • Wiskott-Aldrich syndrome - An X-linked disease involving variable degrees of B and T lymphocyte immunodeficiency. Characterized by eczema, thrombocytopenia, and increased susceptibility to bacterial infection - especially by encapsulated organisms such as haemophilus and pneumococcus. Patients who do not succumb to infections are at increased risk of developing malignant lymphomas. The only treatment for Wiskott-Aldrich syndrome is bone marrow transplantation.

   • Ataxia-Telangiectasia (AT) - An autosomal recesssive genetic disorder that affects a number of cells in the body includng T and B lymphocytes. The immunologic abnormalities involve defects in both humoral and cell-mediated immunity. Like many other primary immunodeficiency disorders, onset occurs during childhood. Non-immunologic problems associated with this condition include cerebellar ataxia, muscle atrophy, cutaneous and scleral telangiectaisia, and increased risk for malignancies later in life. The increased risk for malignancy is due to defective DNA repair associated with the mutant AT gene. Because of this, patients with AT should avoid exposure to x-rays. Treatment is largely supportive. As in all patient's with defective T Lymphocyte function, live vaccines and blood transfusions containing viable T cells must be avoided. PCP prophylaxis with trimethoprim-sulfa is often provided to these patients.

   • Other - Inherited defects in the complement system, and defects in granulocyte function are rarer causes of primary immunodeficiency. Complement disorders are associated with increased risk for pyogenic infection - especially infection by Neisseria species. WBC defects lead to chronic granulomatous infections of the skin, lungs, lymph nodes, and other organs.

   
   

2. Secondary immunodeficiencies: More common than primary immunodeficiencies. These are acquired defects in immune function resulting from:
   • Drugs - Many cancer chemotherapy drugs (especially alkylating agents) injure stem cells in the bone marrow leading to neutropenia and increased risk for infection. Immunosuppressive therapy - drugs used to intentionally suppress the immune system in order to treat autoimmune diseases or prevent rejection of transplanted organs. Corticosteroids interfere with the development and function of lymphocytes and granulocytes.

   • Microbial Infections - Many pathogens have evolved mechanisms for surviving by suppressing the immune system of their host. Examples include measles, herpesvirus, some species of staphylococci and streptococci, chronic mycobacterial and parasitic infections. HIV infection produces profound defects in both humoral and T Cell-mediated immunity because it targets the CD4 positive Helper T Lymphocyte - a cell that plays a crucial role in all aspects of specific acquired immunity. Immune defects associated with HIV infection include: impaired cell-mediated cytotoxicity by CD8-positive T lymphocytes, depressed immunoglobulin synthesis due to ineffective B lymphocyte activation, decreased delayed type hypersensitivity, impaired functioning of macrophages (reduced chemotaxis, phagocytosis, and antigen presentation), decreased tumor killing by NK cells.

   • Disseminated cancers - Malignancies that invade the bone marrow may injure immune system cells and their precursors. Some cancers may also produce substances that interfere with the normal development and differentiation of lymphocytes. (E.g., Hodgkin disease, chronic lymphocytic leukemia, multiple myeloma)

   • Malnutrition - The basis for defective humoral and cell-mediated immune responses seen in poorly nourished individuals is not clearly defined. However, much of the morbidity and mortality afflicting the malnourished worldwide is due to infections.

   • Other: - Environmental toxins (pesticides, benzene, polychlorinated biphenyls, heavy metals, etc.). Radiation therapy (bone marrow suppression, lymphocyte toxicity). Splenectomy (increased susceptibility to infection by encapsulated microorganisms). Severe burns (loss of immunoglobulins through damaged skin). Chronic renal disease, diabetes mellitus, chronic liver disease.

Laboratory Evaluation of Patients with Suspected Immunodeficiency

1. Defects in B Lymphocytes and Humoral Immunity
   • Quantitative serum immunoglobulins - Measurement of the serum concentration of the major classes of immunoglobulins. Most B cell defects are associated with diminished concentrations of IgG, IgM, or IgA.

   • Immunologic challenge - Measuring the concentrations of specific antibodies after immunization with common antigens (tetanus, diphtheria, capsular polysaccaride of hemophilus influenza type B or pneumococcus).Patients with defective humoral immunity may not be able to produce measurable antibodies in response to these antigens.

   • Total serum complement - Because complement deficiency can mimic B lymphocyte defects, total complement levels (also called total hemolytic complement or CH50) should be measured in all patients with recurring bacterial infections.

2. Defects in T Lymphocytes and Cell-mediated Immunity
   • Complete blood count with differential blood smear - Evaluating for abnormally low lymphocyte counts (lymphopenia) or other hematologic abnormalities associated with some immunodeficiency states.

   • Flow Cytometry - A method of determining lymphocyte subpopulations in patients with lymphopenia (i.e., quantification of B lymphocytes, CD4 positive T lymphocytes and CD8 positive T lymphocytes). Blood cells are mixed with fluorescent monoclonal antibodies that bind specific cell surface markers associated with the various functional categories of lymphocytes. The flow cytometer detects fluorescence and counts the number of cells that bind specific monoclonal antibodies.

   • Skin Testing - Defective delayed-type hypersensitivity (mediated by CD4+ T Lymphocytes) can be evaluated by intradermal injections of PPD, histoplasmosis, mumps, candida, or tetanus toxoid. Inability to mount a skin reaction is called anergy.

   • T Lymphocyte Function - Assessing the ability of T lymphocytes to proliferate in response to specific antigenic challenge, or in response to non-specific cell division stimulants (mitogens). Cells in a lymphocyte culture are treated with radioactive thymidine. Dividing T lymphocytes take up the radio-tracer. The extent of proliferation is determined by measuring radioactivity taken up by cells. Diminished or absent proliferation indicates abnormal T lymphocytre function.