Immunodeficiency Syndromes

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Background

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Background
• Increased susceptibility to infections
• Reactivation of latent infections
• Increased incidence of certain cancers
• Congenital/Primary
• Genetic abnormalities in components of immune system
• Acquired/Secondary
• Results from infection, nutritional deficits, medical treatments

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LAD I

all

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• LADI--most common
• Pathogenesis = absence or defect in beta 2-integrin (CD18) family
• Clinical manifestations = recurrent bacterial infections, particularly of the skin and mucosa; leukocytosis; periodontitis**; no pus formation; impaired wound healing
• Diagnosis = absence of CD18 and the associated alpha subunits on the leukocyte surface by flow cytometry
• Treatment = aggressive management with antibiotics; appropriate vaccinations; careful oral hygiene

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LADII (rare)

all

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LADII (rare)
• Pathogenesis = absence of fucosylated carbohydrate ligands for selectins
• Clinical manifestations = less severe and fewer infections than LADI; severely mentally retarded; short in stature with some facial deformities; delays in motor development
• Diagnosis = physical features, mental and growth retardation, recurrent but usually mild infections, marked leukocytosis, and the ***Bombay blood group
• Treatment = antibiotics and fucose supplementation

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LADIII (rare)

all

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LADIII (rare)
• Pathogenesis = defective activation of all beta–integrins
• Clinical manifestations = infections similar to LADI with bleeding complications
• Diagnosis = bleeding complications from birth, severe bacterial infections, leukocytosis, demonstration of impaired integrin activation
• Treatment = bone marrow or hematopoetic stem cell transplantation

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Leukocyte Adhesion Deficiency (LAD)

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• Leukocytes, particularly neutrophils, cannot migrate from blood vessel into tissues
• Autosomal, recessive

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Chronic Granulomatous Disease (CGD)

Path

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• Impaired phagocytic killing mechanisms of neutrophils and macrophages
• 70% X-linked recessive
• Pathogenesis
• Lack of a NADPH oxidase subunits (gp91phox or p22phox)
• Lack of adapter/ activating proteins (p47phox, p67phox, or p40phox)

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Chronic Granulomatous Disease (CGD)

Clinical manifestations

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• Deep tissue bacterial and fungal abscesses
• Catalase-positive bacteria (S. aureus and Serratia marcescens)
• Burkholderia cepacia
• Aspergillus fumigatus

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Chronic Granulomatous Disease (CGD)

Diagnosis

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• Recurrent and/or unusually severe infections caused by the pathogens commonly associated with CGD
• Neutrophil function tests
• Dihydrorhodamine 123 (DHR) test
• Nitroblue tetrazolium (NBT) test
• Genetic testing

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Chronic Granulomatous Disease (CGD)

Treatment

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Prophylaxis with trimethoprim/sulfamethoxazole

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Chronic Granulomatous Disease (CGD)

Lack of a NADPH oxidase subunits

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• Lack of a NADPH oxidase subunits (gp91phox or p22phox)

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Chronic Granulomatous Disease (CGD)

Lack of adapter/ activating proteins

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Lack of adapter/ activating proteins (p47phox, p67phox, or p40phox)

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Defects in Lymphocyte Maturation

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Severe Combined Immunodeficiency Disorder (SCID)
DiGeorge Syndrome

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Severe Combined Immunodeficiency Disorder (SCID)
• Pathogenesis

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Pathogenesis
• Cytokine signaling deficiency
• Purine metabolism deficiency
• Defective lymphocyte receptor rearrangements

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Severe Combined Immunodeficiency Disorder (SCID)

Clinical manifestations

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Clinical manifestations
• Within 3-6 months of life
• Recurrent oral candidiasis, failure to thrive, and protracted diarrhea and/or acute interstitial pneumonitis caused by Pneumocystis jiroveci

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Severe Combined Immunodeficiency Disorder (SCID)

Treatment

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• Hematopoetic stem cell transplant
• Aggressive treatment of infections

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Severe Combined Immunodeficiency Disorder (SCID)

Diagnosis

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Determination of number of circulating T, B, and NK cells

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Severe Combined Immunodeficiency Disorder (SCID)
• Pathogenesis
1. Cytokine signaling deficiency
2. Purine metabolism deficiency
3. Defective lymphocyte receptor rearrangements

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1. gamma receptor --paired with IL7 and IL2 , w/o signal from IL2/7 you dont get clonal expansion, maturation, adaptation of adaptive arm of Immune system
2.cant make nucleic acids, block
3.t-cell/bcell receptors for antigens-->lymphocyte will die w/ no immune response

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DiGeorge Syndrome
• Pathogenesis

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• Heterozygous chromosomal deletion at 22q11.2 resulting in abnormal development of the embryonic pharyngeal system (thymus)
• 90% heterozygous for microdeletion

CATCH22: Cardiac Abnormality (especially tetralogy of Fallot), Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism.

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DiGeorge Syndrome

Clinical manifestations

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Clinical manifestations
• Developmental delay, conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia
• Mild T cell number deficits to complete absence
• Humoral deficits secondary to T cell defects
• Sinopulmonary infections

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DiGeorge Syndrome

Diagnosis

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Diagnosis
• Reduced numbers of CD3+ T cells with characteristic triad of features (conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia)
• Demonstrated deletion in chromosome 22q11.2

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DiGeorge Syndrome

Treatment

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Treatment
• Multidisciplinary team including cardiologist, endocrinologist, otolaryngologist, speech/language pathologist, developmental pediatric specialist, and an immunologist

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Defects in Lymphocyte Activation and Function
• Common Variable Immunodeficiency Disorder (CVID)

Path

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Pathogenesis
• Impaired B cell differentiation with defective antibody production
• Collection of hypogammaglobulinemias

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Defects in Lymphocyte Activation and Function
• Common Variable Immunodeficiency Disorder (CVID)

Clinical manifestations

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Clinical manifestations
• Recurrent infections, chronic lung disease, autoimmune disorders, gastrointestinal disease, lymphoma
• Markedly reduced serum IgG with low levels of IgA and/or IgM

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Defects in Lymphocyte Activation and Function
• Common Variable Immunodeficiency Disorder (CVID)

Diagnosis

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Diagnosis
• Significantly reduced total serum IgG
• Low IgA and/or IgM
• Poor or absent response to immunization

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Defects in Lymphocyte Activation and Function
• Common Variable Immunodeficiency Disorder (CVID)

Treatment

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Treatment
• IG replacement therapy
• Prophylactic antimicrobials

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Lymphocyte Abnormalities Associated with Other Diseases
• Wiskott-Aldrich Syndrome

Pathogenesis

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• X-linked disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp)
• Affects cytoskeletal proteins leading to deficits in immunologic synapse (where ag presenting cells and t-cells come together)
• Impaired T cell migration, adhesion, and interaction with other immune cells

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Lymphocyte Abnormalities Associated with Other Diseases
• Wiskott-Aldrich Syndrome

Clinical manifestations

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Clinical manifestations
• Classic: early in childhood with thrombocytopenia; recurrent bacterial, viral and fungal infections; and extensive eczema***
• X-linked thrombocytopenia
• X-linked neutropenia

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Lymphocyte Abnormalities Associated with Other Diseases
• Wiskott-Aldrich Syndrome

Diagnosis

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Diagnosis
• Decreased number and function of T cells
• Abnormal immunoglobulin isotypes, notably low to normal IgG and IgM and high IgA and IgE
• Defective antibody responses to some vaccine antigens
• Normal to increased natural killer (NK) cell numbers, but reduced cytotoxicity
• Decreased function of regulatory T (Treg) cells
• Impaired chemotaxis of phagocytic cells

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Lymphocyte Abnormalities Associated with Other Diseases
• Wiskott-Aldrich Syndrome

Treatment

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Treatment
• Platelet transfusions and prophylactic antimicrobials
• IVIG
• Hematopoetic stem cell transplant

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Ataxia Telangiectasia
• Pathogenesis

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Lymphocyte Abnormalities Associated with Other Diseases
• Autosomal recessive disorder associated with defective DNA repair mechanisms
• Chromosome 11q22.3

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Ataxia Telangiectasia

Clinical manifestations

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Clinical manifestations
• Progressive cerebellar ataxia, abnormal eye movements, oculocutaneous telangiectasias, and immune deficiency affecting both cellular and humoral immunity
• Recurrent sinopulmonary infections

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Ataxia Telangiectasia

Diagnosis

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Diagnosis
• Immunoglobulin deficiency, especially absence or marked reduction of IgA, IgG2, and other IgG subclasses
• Inability to produce antibodies to polysaccharide antigens (bacterial capsule-->neisseria, h. inf, strep)
• Oligoclonal gammopathy (ab production wild, INCR and random)
• T cell lymphopenia

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Ataxia Telangiectasia

Treatment

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Treatment
• Surveillance and prevention of infections and dysphagia (sinopulmonary cause)