Primary Immunodeficiency Primary Immunodeficiency Diseases Diseases

The primary immunodeficiency diseases The primary immunodeficiency diseases are a group of disorders in which the are a group of disorders in which the

primary defect appears to be intrinsic to primary defect appears to be intrinsic to one or more components of the immune one or more components of the immune

system. system.

The immune system functional The immune system functional compartmentscompartments

• The B-lymphocyte system The B-lymphocyte system

• The T-lymphocyte system The T-lymphocyte system

• The Phagocytic system The Phagocytic system

• The Complement systemThe Complement system

Frequency of the Primary Frequency of the Primary

Immunodeficiency DiseasesImmunodeficiency Diseases

• The primary immunodeficiency The primary immunodeficiency diseases were originally thought to diseases were originally thought to be quite rare. be quite rare.

• some of the primary some of the primary immunodeficiency diseases are immunodeficiency diseases are relatively common.relatively common.

• For example, Selective IgA For example, Selective IgA deficiency occurs in as many as deficiency occurs in as many as 1/500-1/1000 individuals.1/500-1/1000 individuals.

Frequency of the Primary Frequency of the Primary Immunodeficiency DiseasesImmunodeficiency Diseases

• Other primary immunodeficiency diseases Other primary immunodeficiency diseases are much less common and occur with a are much less common and occur with a frequency of between 1/10,000 and frequency of between 1/10,000 and 1/100,000. 1/100,000.

• Because there are so many primary Because there are so many primary immunodeficiency diseases, when taken immunodeficiency diseases, when taken together as a group of disorders, they together as a group of disorders, they become a significant health problem, become a significant health problem,

• occurring with a frequency comparable to occurring with a frequency comparable to leukemia and lymphoma in children and four leukemia and lymphoma in children and four times as frequently as cystic fibrosistimes as frequently as cystic fibrosis..

Causes of the Primary Causes of the Primary Immunodeficiency Diseases Immunodeficiency Diseases

• Many of the primary Many of the primary immunodeficiency diseases are immunodeficiency diseases are genetically determined. genetically determined.

• Some of these are inherited as Some of these are inherited as autosomal recessive traits, some as autosomal recessive traits, some as X-linked recessive traits, and at least X-linked recessive traits, and at least one is inherited as an autosomal one is inherited as an autosomal dominant trait.dominant trait.

Causes of the Primary Causes of the Primary Immunodeficiency DiseasesImmunodeficiency Diseases

• Others are not inherited as single gene Others are not inherited as single gene defects. In fact, two of the most common defects. In fact, two of the most common primary immunodeficiency diseases, primary immunodeficiency diseases, Common Variable Immunodeficiency Common Variable Immunodeficiency (CVID) and Selective IgA Deficiency, (CVID) and Selective IgA Deficiency, usually occur sporadically and do not usually occur sporadically and do not appear to be due to single gene defects in appear to be due to single gene defects in most cases.most cases.

• However, there are even some rare cases However, there are even some rare cases of Common Variable Immunodeficiency of Common Variable Immunodeficiency Disease and Selective IgA Deficiency that Disease and Selective IgA Deficiency that occur in a familial setting. occur in a familial setting.

Clinical Manifestations of the Clinical Manifestations of the Primary Immunodeficiency Primary Immunodeficiency

DiseasesDiseases

• INFECTIOUS DISEASESINFECTIOUS DISEASES

• AUTOIMMUNE AND RHEUMATIC AUTOIMMUNE AND RHEUMATIC DISEASESDISEASES

• GASTROINTESTINAL DISEASE GASTROINTESTINAL DISEASE

• HEMATOLOGIC DISEASES HEMATOLOGIC DISEASES

INFECTIOUS DISEASES INFECTIOUS DISEASES

• An increased susceptibility to infection is An increased susceptibility to infection is the hallmark of the primary the hallmark of the primary immunodeficiency diseases. immunodeficiency diseases.

• In most patients, this is manifested by In most patients, this is manifested by recurrent infections. recurrent infections.

• Typically, the infections do not occur only Typically, the infections do not occur only in a single anatomic site, but usually in a single anatomic site, but usually involve multiple organs or multiple sites involve multiple organs or multiple sites within the same organ.within the same organ.

INFECTIOUS DISEASESINFECTIOUS DISEASES

• Recurrent otitis media in association with Recurrent otitis media in association with recurrent sinusitis and/or pneumonia, while recurrent sinusitis and/or pneumonia, while other patients may have recurrent pneumonia, other patients may have recurrent pneumonia, with episodes occurring in different lobes. with episodes occurring in different lobes.

• Recurrent sinopulmonary infections, such as Recurrent sinopulmonary infections, such as otitis, sinusitis, bronchitis, and pneumonia, are otitis, sinusitis, bronchitis, and pneumonia, are the most common presenting manifestations the most common presenting manifestations of the primary immunodeficiency diseasesof the primary immunodeficiency diseases

• but recurrent systemic infections such as but recurrent systemic infections such as bacteremia and meningitis are also seen.bacteremia and meningitis are also seen.

INFECTIOUS DISEASESINFECTIOUS DISEASES

• Chronic changes of the lungs and sinuses Chronic changes of the lungs and sinuses are not unusual. In many instances, the are not unusual. In many instances, the patients not only have recurrent infections, patients not only have recurrent infections, but one or more of these is eitherbut one or more of these is either

• unusually severe, leads to an unexpected unusually severe, leads to an unexpected or unusual complication, or is caused by an or unusual complication, or is caused by an organism of relatively low virulence (i.e. an organism of relatively low virulence (i.e. an opportunistic organism). opportunistic organism).

• some patients the first infection may be so some patients the first infection may be so severe or unusual that it raises the severe or unusual that it raises the question of an underlying question of an underlying immunodeficiency. immunodeficiency.

INFECTIOUS DISEASESINFECTIOUS DISEASES

• The type of infectious agent and the location The type of infectious agent and the location of the infection may give valuable insight into of the infection may give valuable insight into the nature of the immunologic defect.the nature of the immunologic defect.

• For example, individuals who have B-cell For example, individuals who have B-cell deficiencies characteristically have an deficiencies characteristically have an increased susceptibility to infection with increased susceptibility to infection with encapsulated pyogenic bacteria, such as the encapsulated pyogenic bacteria, such as the pneumococcus and H.influenzae, and to pneumococcus and H.influenzae, and to enteroviruses.enteroviruses.

• Patients who are deficient in T-cells may have Patients who are deficient in T-cells may have infections with a variety of microorganisms infections with a variety of microorganisms but appear especially susceptible to fungi, but appear especially susceptible to fungi, viruses and Pneumocystis.viruses and Pneumocystis.

•

INFECTIOUS DISEASESINFECTIOUS DISEASES

• Patients with complement deficiencies Patients with complement deficiencies often present with blood- borne often present with blood- borne infections, such as bacteremia and infections, such as bacteremia and meningitis, caused by encapsulated meningitis, caused by encapsulated bacteria. bacteria.

• patients with phagocytic disorders patients with phagocytic disorders characteristically have infections of the characteristically have infections of the skin and reticuloendothelial system.skin and reticuloendothelial system.

AUTOIMMUNE AND RHEUMATIC AUTOIMMUNE AND RHEUMATIC DISEASES DISEASES • rheumatoid arthritis, systemic lupus rheumatoid arthritis, systemic lupus

erythematosus, and/or dermatomyositis. erythematosus, and/or dermatomyositis. • Autoimmune and rheumatic diseases are Autoimmune and rheumatic diseases are

more commonly seen in some of the primary more commonly seen in some of the primary immunodeficiency diseases than in others.immunodeficiency diseases than in others.

• For example, they are relatively common in For example, they are relatively common in Selective IgA Deficiency, Common Variable Selective IgA Deficiency, Common Variable Immunodeficiency and deficiencies of the Immunodeficiency and deficiencies of the complement system complement system

• Relatively uncommon in X-linked Relatively uncommon in X-linked agammaglobulinemia. agammaglobulinemia.

GASTROINTESTINAL GASTROINTESTINAL DISEASE DISEASE • Chronic diarrhea, malabsorption and even Chronic diarrhea, malabsorption and even

malnutrition may be important manifestations malnutrition may be important manifestations of primary immunodeficiency diseases, of primary immunodeficiency diseases, especially in infants and young children.especially in infants and young children.

• infectious. Chronic giardiasis, rotavirus and infectious. Chronic giardiasis, rotavirus and cryptosporidium, among other infections, cryptosporidium, among other infections, have each been significant problems in have each been significant problems in patients with primary immunodeficiency patients with primary immunodeficiency diseases. diseases.

• non infectious etiology includes inflammatory non infectious etiology includes inflammatory bowel disease, gluten-sensitive enteropathy, bowel disease, gluten-sensitive enteropathy, atrophic gastritis with pernicious anemia and atrophic gastritis with pernicious anemia and nodular lymphoid hyperplasia. nodular lymphoid hyperplasia.

HEMATOLOGIC DISEASES HEMATOLOGIC DISEASES

• Anemia, thrombocytopenia, or Anemia, thrombocytopenia, or leukopenia are seen frequently in leukopenia are seen frequently in patients with primary immunodeficiency patients with primary immunodeficiency diseases. diseases.

• For example, the Wiskott-Aldrich For example, the Wiskott-Aldrich Syndrome is characterized by variable Syndrome is characterized by variable defects in B-lymphocyte and T-defects in B-lymphocyte and T-lymphocyte function. These patients lymphocyte function. These patients also have intrinsic abnormalities of their also have intrinsic abnormalities of their platelets which result in small platelets platelets which result in small platelets and significant thrombocytopenia. and significant thrombocytopenia.

• . .

HEMATOLOGIC DISEASESHEMATOLOGIC DISEASES

• hematologic abnormalities in consequence hematologic abnormalities in consequence of the autoimmune diseases that are seen in of the autoimmune diseases that are seen in patients with primary immunodeficiency. For patients with primary immunodeficiency. For example, a significant proportion of patients example, a significant proportion of patients with autoimmune hemolytic anemia or ITP with autoimmune hemolytic anemia or ITP

• Autoimmune hemolytic anemia, and/or Autoimmune hemolytic anemia, and/or thrombocytopenia, and/or neutropenia are thrombocytopenia, and/or neutropenia are often seen in patients with Common often seen in patients with Common Variable Immunodeficiency or Selective IgA Variable Immunodeficiency or Selective IgA Deficiency, and the hyper IgM SyndromeDeficiency, and the hyper IgM Syndrome

Laboratory Diagnosis of Laboratory Diagnosis of Immunodeficiency Immunodeficiency

• EVALUATION OF B-LYMPHOCYTE EVALUATION OF B-LYMPHOCYTE FUNCTION: FUNCTION: The initial screening test for B-lymphocyte The initial screening test for B-lymphocyte function is the measurement of serum function is the measurement of serum immunoglobulines. immunoglobulines.

• Quantitative measurements of serum IgG, Quantitative measurements of serum IgG, IgA and IgM will identify patients with IgA and IgM will identify patients with panhypogammaglobulinemia as well as panhypogammaglobulinemia as well as patients who have a deficiency of an patients who have a deficiency of an individual class of immunoglobulin, such individual class of immunoglobulin, such as selective IgA deficiency. as selective IgA deficiency.

Laboratory Diagnosis of Laboratory Diagnosis of ImmunodeficiencyImmunodeficiency

• There are four subclasses of IgG There are four subclasses of IgG

• In some instances, the total serum In some instances, the total serum IgG may be normal or near normal IgG may be normal or near normal but the patient may still have an IgG but the patient may still have an IgG subclass deficiency. subclass deficiency.

Laboratory Diagnosis of Laboratory Diagnosis of ImmunodeficiencyImmunodeficiency

• assessment of antibody function is a necessary assessment of antibody function is a necessary part of the evaluation of humoral immunity.part of the evaluation of humoral immunity.

• Antibody titers after immunization with protein Antibody titers after immunization with protein antigens (e.g. tetanus or diphtheria toxoids) and antigens (e.g. tetanus or diphtheria toxoids) and polysaccharide (e.g. pneumococcal capsular polysaccharide (e.g. pneumococcal capsular polysaccharides) are most convenient. polysaccharides) are most convenient.

• If immunoglobulin levels and/or antibody titers If immunoglobulin levels and/or antibody titers are decreased, the evaluation should proceed are decreased, the evaluation should proceed with more advanced tests of B-lymphocyte with more advanced tests of B-lymphocyte numbers and function. numbers and function.

Laboratory Diagnosis of Laboratory Diagnosis of ImmunodeficiencyImmunodeficiency

• EVALUATION OF T-LYMPHOCYTE FUNCTION: EVALUATION OF T-LYMPHOCYTE FUNCTION: Testing for defects in T-lymphocyte function Testing for defects in T-lymphocyte function is relatively difficult because of the lack of is relatively difficult because of the lack of inexpensive and reliable screening tests. inexpensive and reliable screening tests.

• Delayed type hypersensitivity (DTH) skin Delayed type hypersensitivity (DTH) skin tests using a panel of ubiquitous antigens can tests using a panel of ubiquitous antigens can be used as a screening test in older children be used as a screening test in older children and adults. and adults.

• The presence of a positive DTH skin test The presence of a positive DTH skin test generally indicates intact T-cell function and generally indicates intact T-cell function and cell mediated immunity. cell mediated immunity.

Laboratory Diagnosis of Laboratory Diagnosis of ImmunodeficiencyImmunodeficiency

• More specialized tests of T-cell function More specialized tests of T-cell function include an assessment of lymphocyte include an assessment of lymphocyte proliferation in response to nonspecific proliferation in response to nonspecific mitogens (e.g. phytohemagglutinin), mitogens (e.g. phytohemagglutinin), specific antigens (e.g. candida) and/or specific antigens (e.g. candida) and/or mononuclear cells from an unrelated, mononuclear cells from an unrelated, histoincompatible individual (mixed histoincompatible individual (mixed leukocyte reaction). leukocyte reaction).

• It is also possible, in specialized It is also possible, in specialized laboratories, to measure the production of laboratories, to measure the production of a number of different cytokines that are a number of different cytokines that are involved in T- and B- lymphocyte involved in T- and B- lymphocyte regulation (e.g. Interleukin 2, interferon-regulation (e.g. Interleukin 2, interferon-gamma).gamma).

Laboratory Diagnosis of Laboratory Diagnosis of ImmunodeficiencyImmunodeficiency

EVALUATION OF PHAGOCYTIC FUNCTIONEVALUATION OF PHAGOCYTIC FUNCTION

• reductions in phagocytic cell number in reductions in phagocytic cell number in the peripheral blood and, therefore, can be the peripheral blood and, therefore, can be detected by using a white blood cell count detected by using a white blood cell count and differential. and differential.

• measuring the reduction of nitroblue measuring the reduction of nitroblue tetrazolium (NBT test). tetrazolium (NBT test).

EVALUATION OF THE EVALUATION OF THE COMPLEMENT SYSTEMCOMPLEMENT SYSTEM

• CH50 assay , this assay requires the CH50 assay , this assay requires the functional integrity of C1 through C9. functional integrity of C1 through C9.

• The identification of the individual The identification of the individual component which is deficient rests component which is deficient rests on specialized functional and on specialized functional and immunochemical tests which are immunochemical tests which are specific for each component. specific for each component.

Primary Immune Deficiency Primary Immune Deficiency DiseasesDiseases

• X-Linked X-Linked AgammaglobulinemiaAgammaglobulinemiaCommon Variable Immune Deficiency DiseCommon Variable Immune Deficiency Diseasease

Selective IgA DeficiencySelective IgA DeficiencySevere Combined Immune DeficiencySevere Combined Immune DeficiencyChronic Granulomatous DiseaseChronic Granulomatous DiseaseThe Wiskott-Aldrich SyndromeThe Wiskott-Aldrich SyndromeThe X-Linked Hyper IgM SyndromeThe X-Linked Hyper IgM SyndromeThe DiGeorge SyndromeThe DiGeorge SyndromeIgG Subclass DeficiencyIgG Subclass DeficiencyAtaxia TelangiectasiaAtaxia Telangiectasia