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Primary immunodeficiencies Prof.Dr. Yıldız Camcıoğlu 10 Signs and symptoms of PID 1- More than 8 infections per year 2- More than 2 sinus infections per year 3- Uneffective antibiotic treatment more than 2 months 4- More than 8 pneumonias per year 5- Growth retardation 6- Recurrent deep tissue or organ abscesses 7- Persistant mucosal or skin fungal infections after first year of age 8- Need for IV antibiotic therapy 9- More than 2 deep tissue infections per year 10- PID in family Spesific signs • • • • • • • • • Telangiectasia Ataxia Short-limped dwarftism Cartilage-hair hypoplasia Idiopatic endocrinopathy Partial albinism Trombocytopeni Tetany Eczema Assessment General • • • • Patient and family history Physical examination Laboratory assesment Treatment The family history • PID in the family; familial occurrence of similar symptoms (affected males related by the female line, or another clear pattern of inheritance) • Unexplained early infant deaths, deaths due to infection • Consanguinity in the (grand) parents (known or suspected) • Autoimmune disease or haematological malignancy in several family members Physical examination • Skin and appendages • Abnormal hair or teeth. Eczema. Neonatal erythroderma. (Partial) albinism. Pale skin. Incontinentia pigmenti. Nail dystrophy. • Extensive warts or molluscae. Congenital alopecia. Vitiligo. Petechiae (early onset, chronic). Cold abscesses. Telangiectasia. • Absence of sweating • Oral cavity Gingivostomatitis (severe). Periodontitis. Aphthae (recurrent). Giant oral ulcers. Thrush. Dental crowding. Conical incisors. • Enamel hypoplasia. Persistent deciduous teeth • Eyes Retinal lesions. Telangiectasia • Lymphoid tissue Absence of lymph nodes and tonsils. Lymphadenopathy (excessive). Asplenia. Organomegaly (liver, spleen) • Neurological Ataxia. Microcephaly. Macrocephaly • Other Angioedema (without urticaria). Digital clubbing. Dysmorphism. Stunted growth or disproportional growth Primary Immunodeficiency Diseases International Union of Immunological Societies Primary Immunodeficiency Diseases Classification I-Combined T- and B-cell immunodeficiencies II-Predominantly antibody deficiencies III-Other well-defined immunodeficiency syndromes IV-Diseases of immune dysregulation V-Congenital defects of phagocyte number, function, or both VI-Defects in innate immunity VII-Autoinflammatory disorders VIII-Complement deficiencies I-Predominantly antibody deficiencies • 1. Severe reduction in all serum Ig isotypes with absent B cells (a) Btk deficiency (b) m heavy chain deficiency (c) l 5 deficiency (d) Igα deficiency (e) BLNK deficiency (f) Thymoma with immunodeficiency • 2. Severe reduction in at least 2 serum Ig isotypes with normal or low numbers of B cells (a) Common variable immunodeficiency disorders (b) ICOS deficiency (c) CD19 deficiency (d) TACI deficiency(e) BAFF receptor deficiency Predominantly antibody deficiencies • 3. Severe reduction in serum IgG and IgA with increased IgM and normal numbers of B cells (a) AID deficiency(b) UNG deficiency • 4. Isotype or light chain deficiencies with normal numbers of B cells (a) Ig heavy chain deletions (b) κ Chain deficiency (c) Isolated IgG subclass deficiency (d) IgA with IgG subclass deficiency (e) Selective IgA deficiency • 5. Specific antibody deficiency with normal Ig concentrations and numbers of B cells • 6. Transient hypogammaglobulinemia of infancy B-Cell defects; clinical findings • • • • • • • Infections onsets after 6 months of age Adenoids and tonsils are rudimentary Lymph nodes are reduced in size Chronic pulmonary diseases Recurrent otitis media Bronchiectasia Encapsulated microorganisms S.pneumoniae H.influenzae typ b N.meningitidis X-linked agammaglobulinemia (XLA) • XLA is the first primary immunodeficiency disease reported by Bruton in1952 • Affected persons develop severe, recurrent sinus and pulmonary infections and septicemias with bacteria usually during the first year of life • Patients have a few antibody-producing B cells • Antibody production is defective Common variable Immunodeficiency • CVID is characterized by variably low levels of immunoglobulin G (IgG), immunoglobulin M (IgM), and IgA, • Antibody responses after vaccination is suboptimal • Patients usually experience recurrent bouts of pneumonia and infections of the joints, bones, and skin • These persistent infections lead to organ damage, often resulting in disability or death from chronic lung disease • CVID had increased risk for lymphomas Isolated IgA deficiency • IgA deficieny has a wide clinical spectrum • Certain persons are asymptomatic whereas other have recurrent infections • Some patients also have IgG subclass deficiencies • The incidence of allergy or autoimmune disease is increased among patients with selective IgA deficiency • IgA-deficient persons might have severe or fatal anaphylactic reactions to blood or blood-products containing IgA IgG Subclass deficiency • IgG1 deficiency; CVID, isolated IgA deficiency • IgG2 deficiency; with or without IgG4 deficiency, with isolated IgA deficiency • IgG3 deficiency; with or without IgG1 deficiency Laboratory Tests General approach; WBC, Lymphocyte , neutrophil count Microbiologic studies ; culture Humoral immune deficiencies; Serum IgG, IgM. IgA levels Isohemaggulitinin titers Spesific antibody response (tetanus,dyphteria,Hib) WBC, Leucocyte morphology, trombocyte, reticulocyte count Haemolytic anemia G6PD deficiency Anormal neutrophil granul+ partial albinis Chediak-Higashi Syndrome Anormal neutrophil granuls(Pelger-Huet anomalisi) Spesific Granul deficiency Howell-Jolly bodies Asplenia Trombocytopenia+Eczema Wiskott-Aldrich Sendromu Neutrophil count1500 Neutropenia, cyclic neutropenia NORMAL B-Cell Function Screening Tests • Serum immunoglobulin levels • Serum specific antibody titers • Antibody response to booster immunization • Flow cytometry to enumerate B cells • In vitro immunoglobulin production in response to mitogen • In vitro immunoglobulin production in response to anti-CD40 and cytokines Immunoglobulin levels IgG+A+M 400mg/dL Normal, or 2SD Mildly low 400mg/dL T.protein, albumin response Specific antibody (TT, İsohemagglutinin, PPS) IgG subclassews Normal Low immunised Low production Primary Immune Def.. IgG half life Abnormal Low Sekondary Imm. Def. İnfections with IgG subclass Antibody def. RicardoSorensen: Pediatric Clinics of North America, 2000 Normal IgG, IgG subclasses,IgM, IgA,IgE levels Antibody levels( tetanus, dyphteria, H.influenzae) Low immunoglobulins Normal immunoglobulins levels XLA Antibody deficiency syndrome CVI IgA deficiency IgG subclass deficiency IgM deficiency Transient hypogammaglobulinemia of infancy High immunoglobulins Hyper IgE Hyper IgM Syndrome AIDS B-Cell Defects Agammaglobulinemia Transient HypogammaGlobulinemia of infancy(THI) Common variable immune deficiency (CVID) B cell 0-2 % IgG 100 mg/dl IgA 0-10 mg/dl IgM 0-20 B cell 10-20 % IgG 250 mg/dl IgA 10 mg/dl IgM 20 mg/dl B cell 10-20% IgG 250 mg/dl IgA 20 mg/dl IgM 60 mg/dl Management of Humoral immunodeficiencies • Intravenous immunoglobulin (IVIG) replacement therapy • Avoidance of live viral vaccines • Systemic antibiotics • Patient/parent education and genetic counseling IVIG Therapy • • • • • • • • X-linked Agammaglobulinemia THI(rarely) CVID Hyper IgM Syndrome Isolated IgA deficiency(Caution?) IgG subclass deficiencies Antibody response deficiency CID II-Severe Combined immunodeficiencies (SCID) • • • • • Infections onsets at early life Failure to thrive Persistant oral and mucosal fungal infections Chronic CMV, P.Carinii, toxoplasmosis Opportunistic infections Lymphocyte count, Delayed type skin testleri( candidin, tetanus, mumps, tricophyton, streptokinase-streptodornase) Total B and T cell; CD19,CD3,CD4+, CD8+, CD4+/CD8+,CD56 T Lymphocyte proliferation test Timus X ray SCID Lymphopenia ( < 1500/mm3), Peripheral CD3 (+) , T cell count < 20 %(< 500/mm3) B and NK cell counts variable Poor Lymphocyte proliferation response to PHA or mitogen Hypogammaglobulinemia ( <150mg/dl IgG) Cellular Immune Function Screening Tests • Flow cytometry to enumerate T cells and natural killer cells • Cutaneous delayed hypersensitivity Advanced Tests • Enzyme assays (adenosine deaminase [ADA], purine nucleoside phosphorylase [PNP]) • Fluorescent in situ hybridization (FISH) for 22q11 and 10p11 deletion • In vitro proliferative response to mitogens and antigens • Natural killer cell cytotoxicity • Cytokine production in response to mitogen or antigen stimulation • Expression of surface markers after mitogen stimulation Combined T- and B-cell immunodeficiencies (SCID) T-B-NK- T-B-NK+ T-B+NK- T-B+NK+ Adenosine deaminase deficiency Reticular dysgenesis IgG IgA IgM IgE - X-SCID JAK3 RAG 1 /2 deficiency Omenn syndrome Navajo SCID - IL-7 R ZAP-70 deficiency deficiency deficiency PNP CD3 deficiency - - deficiency ± ± ± - T+B+ - N N N, , N Tip2 BLS IL-2 deficiency + + - ± Management of combined immunodeficiencies • • • • • • HLA-identical (sibling) bone marrow transplantation IVIG Avoidance of nonirradiated blood or products Avoidance of live viral vaccines Pneumocystis prophylaxis Avoidance of cytomegalovirus (CMV)-positive blood or cells • Antifungal agents • Anti-mycobacterial therapy • Patient education and genetic counseling III. Other well-defined immunodeficiency syndromes • 1. Wiskott-Aldrich syndrome • 2. DNA repair defects • (a) Ataxia-telangiectasia (b) Ataxia-like syndrome (c) Nijmegen breakage syndrome (d) Bloom syndrome • 3. Thymic defects Di George anomaly • 4. Immuno-osseous dysplasias (a) Cartilage hair hypoplasia (b) Schimke syndrome • 5. Hermansky-Pudlak syndrome type 2 • 6. Hyper-IgE syndrome • 7. Chronic mucocutaneous candidiasis IV. Diseases of immune dysregulation 1. Immunodeficiency with hypopigmentation (a) Chediak-Higashi syndrome (b) Griscelli syndrome, type 2 2. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes (a) Perforin deficiency (b) Munc 13-D deficiency (c) Syntaxin 11 deficiency 3. X-linked lymphoproliferative syndrome (XLP) 4. Syndromes with autoimmunity (a) Autoimmune lymphoproliferative syndrome (ALPS) (i) CD95 (Fas) defects, type 1a (ii) CD95L (Fas ligand) defects, ALPS type 1b (iii) Caspase 10 defects, ALPS type 2a (iv) Caspase 8 defects, ALPS type 2b (b) APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (c) IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked) V. Congenital defects of phagocyte number, function, or both 1.-3.Severe congenital neutropenias 4.Kostmann syndrome 5.Cyclic neutropenia 6.X-linked neutropenia/myelodysplasia 7.Leukocyte adhesion deficiency type 1 8.Leukocyte adhesion deficiency type 2 9.Leukocyte adhesion deficiency type 3 10.Rac 2 deficiency 11.β-Actin deficiency 12.Localized juvenile periodontitis V. Congenital defects of phagocyte number, function, or both 13.Papillon-Lefèvre syndrome 14.Specific granule deficiency 15.Shwachman-Diamond syndrome 16.X-linked chronic granulomatous disease (CGD) 17.-19.Autosomal CGDs20.Neutrophil G-6PD deficien. 21.IL-12 and IL-23 receptor β1 chain deficiency 22.IL-12p40 deficiency 23.IFN-γ receptor 1 deficiency 24.IFN-γ receptor 2 deficiency 25.STAT1 deficiency (2 forms) Chronic granulomatous disease (CGD) • Caused by a defect in intracellular killing of bacteria by phagocytes • It can be inherited as an X-linked or autosomal-recessive defect • Affected persons experience frequent and severe infections of the skin, lungs, and bones and tumor-like masses called granulomas Leukocyte adhesion defect (LAD), • Phagocytes lack an essential adhesion molecule, preventing them from migrating to sites of infection • The result is recurrent, life-threatening infections, especially of the soft tissues. Phagocytic Cell Function Screening Tests • Blood cell count with differential <500 • Neutrophil staining, morphology Advanced Tests • Oxidase function (nitroblue tetrazolium, chemiluminescence) • Flow cytometry for adhesion molecules • Chemotaxis • Phagocytosis • Enzyme assays (myeloperoxidase, glucose-6phosphate dehydrogenase ((G6PDH)) • Bacterial or fungal killing Nitroblue tetrazolium(NBT) test Superoxide O2 investigation Chemotaxis Rebuck skin window test Abnormal NBT test Abnormal chemotaxis Chronic Granulamatous diseases Complement deficiency LAD Chediak-Higashi Syndrome Specific Granule deficiency NORMAL Management of phagocytic cell disorders • • • • • • • • Avoidance of live bacterial vaccines Antibiotic prophylaxis Interferon gamma Surgical or dental debridement Granulocytic transfusions Antifungals G-CSF BMT VI. Defects in innate immunity Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) IL-1 receptor–associated kinase 4 (IRAK4) deficiency WHIM (warts, hypogammaglobulinemia infections, myelokathexis) syndrome Epidermodysplasia verruciformis VII. Autoinflammatory disorders • Familial Mediterranean fever • TNF receptor–associated periodic syndrome (TRAPS) • Hyper-IgD syndrome • Muckle-Wells syndrome • Familial cold autoinflammatory syndrome • Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) • Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome • Blau syndrome VIII. Complement deficiencies • • • • • • • • • • • C1q deficiency C1r deficiency C4 deficiency C2 deficiency C3 deficiency C5 deficiency C6 deficiency C7 deficiency C8a deficiency C8b deficiency C9 deficiency •C1 inhibitor deficiency •Factor I deficiency •Factor H deficiency •Factor D deficiency •Properdin deficiency •MBP deficiency •MASP2 deficiency Complement Function Screening Tests 1.CH50 (total hemolytic complement activity) 2.AH50 (alternative pathway hemolytic activity) Advanced Tests 1.Level or function of individual complement components 2.Chemotactic activity of complement split products Complement Deficiency • Patients have recurrent and severe infections with encapsulated bacteria, • frequently meningitis • a susceptibility to autoimmune diseases • Terminal complement protein (C6-8) deficiencies are associated with severe infections with Neisseria meningitidis and N. gonorrhoeae Management of complement deficiencies • Pneumococcal vaccine • Meningococcal vaccine • Antibiotic therapy Other Advanced Tests 1.Molecular methods including Southern, Northern, and Western blots, 2.polymerase chain reaction/single-strand conformational polymorphism (PCR/SSCP), DNA fingerprinting, and nucleotide sequencing