Primary immunodeficiencies Prof.Dr. Yıldız Camcıoğlu

1. Primary immunodeficienciesProf.Dr. Yıldız Camcıoğlu

2. 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

3. Spesific signs • Telangiectasia • Ataxia • Short-limped dwarftism • Cartilage-hair hypoplasia • Idiopatic endocrinopathy • Partial albinism • Trombocytopeni  • Tetany • Eczema

4. Assessment General • Patient and family history • Physical examination • Laboratory assesment • Treatment

5. Thefamilyhistory • 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

6. 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

7. Primary ImmunodeficiencyDiseases InternationalUnion of ImmunologicalSocieties PrimaryImmunodeficiencyDiseasesClassification I-Combined T- and B-cellimmunodeficiencies II-Predominantlyantibodydeficiencies III-Otherwell-definedimmunodeficiencysyndromes IV-Diseases of immunedysregulation V-Congenitaldefects of phagocytenumber, function, orboth VI-Defects in innateimmunity VII-Autoinflammatorydisorders VIII-Complementdeficiencies

8. 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

9. 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

10. 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

11. X-linkedagammaglobulinemia (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

12. CommonvariableImmunodeficiency • 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

13. IsolatedIgAdeficiency • 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

14. 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

15. 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)

16. 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+EczemaWiskott-Aldrich Sendromu Neutrophil count1500Neutropenia, cyclic neutropenia NORMAL WBC, Leucocyte morphology, trombocyte, reticulocyte count

17. 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

18. Immunoglobulin levels IgG+A+M 400mg/dLNormal, or  2SD Mildly low  400mg/dL T.protein, albuminSpecific antibody response (TT, İsohemagglutinin, PPS) IgGsubclassews Normal Low immunised Low production IgG half life Primary Abnormal Normal Immune Def.. Low Sekondary Imm. Def. Antibody def. İnfections with IgG subclass RicardoSorensen: Pediatric Clinics of North America, 2000

19. 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

20. B-Cell Defects

21. Management of Humoralimmunodeficiencies • Intravenous immunoglobulin (IVIG) replacement therapy • Avoidance of live viral vaccines • Systemic antibiotics • Patient/parent education and genetic counseling

22. IVIG Therapy • X-linked Agammaglobulinemia • THI(rarely) • CVID • Hyper IgM Syndrome • Isolated IgA deficiency(Caution?) • IgG subclass deficiencies • Antibody response deficiency • CID

23. 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

24. Lymphocyte count, Delayed type skin testleri( candidin, tetanus, mumps, tricophyton, streptokinase-streptodornase) Total B and Tcell;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)

25. 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

26. Combined T- and B-cell immunodeficiencies (SCID)

27. Management of combinedimmunodeficiencies • 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

28. 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

29. 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)

30. 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

31. 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)

32. Chronicgranulomatousdisease (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

33. Leukocyteadhesiondefect (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.

34. 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-6-phosphate dehydrogenase ((G6PDH)) • Bacterial or fungal killing

35. Nitroblue tetrazolium(NBT) test Superoxide O2 investigation Chemotaxis Rebuck skin window test Abnormal NBT test Chronic Granulamatous diseases Abnormal chemotaxis Complement deficiency LAD Chediak-Higashi Syndrome Specific Granule deficiency NORMAL

36. Management of phagocyticcelldisorders • Avoidance of live bacterial vaccines • Antibiotic prophylaxis • Interferon gamma • Surgical or dental debridement • Granulocytic transfusions • Antifungals • G-CSF • BMT

37. 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

38. 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

39. 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

40. Complement Function • Screening Tests • CH50 (total hemolytic complement activity) • AH50 (alternative pathway hemolytic activity) • Advanced Tests • Level or function of individual complement • components • 2.Chemotactic activity of complement • split products

41. 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

42. Management of complementdeficiencies • Pneumococcal vaccine • Meningococcal vaccine • Antibiotic therapy

43. OtherAdvanced Tests • Molecular methods including Southern, Northern, and Western blots, • polymerase chain reaction/single-strand conformational polymorphism (PCR/SSCP), DNA fingerprinting, and nucleotide sequencing