Primary immunodeficiencies Prof.Dr. Yıldız Camcıoğlu
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Transcript of Primary immunodeficiencies Prof.Dr. Yıldız Camcıoğlu
Primary immunodeficiencies
Prof.Dr. Yıldız Camcıoğlu
10 Signs and symptoms of PID
1- More than 8 infections per year2- More than 2 sinus infections per year3- Uneffective antibiotic treatment more than 2 months 4- More than 8 pneumonias per year5- Growth retardation6- Recurrent deep tissue or organ abscesses 7- Persistant mucosal or skin fungal infections after first year
of age 8- Need for IV antibiotic therapy9- More than 2 deep tissue infections per year10- 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
General approach; WBC, Lymphocyte , neutrophil count Microbiologic studies ; cultureHumoral immune deficiencies;
Serum IgG, IgM. IgA levelsIsohemaggulitinin titers
Spesific antibody response (tetanus,dyphteria,Hib)
Laboratory Tests
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
WBC, Leucocyte morphology,trombocyte, reticulocyte count
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 Specific antibody response
(TT, İsohemagglutinin, PPS) IgG subclassews
Normal Low
immunised
Low production IgG half life Primary Abnormal NormalImmune Def.. Low
Sekondary Imm. Def. Antibody def. İnfections with IgG subclass RicardoSorensen: Pediatric Clinics of North America, 2000
IgG, IgG subclasses,IgM, IgA,IgE levelsAntibody levels( tetanus, dyphteria, H.influenzae)
Low immunoglobulins Normal immunoglobulins levels XLA Antibody deficiency syndrome CVI IgA deficiency IgG subclass deficiency IgM deficiencyTransient hypogammaglobulinemia of infancy High immunoglobulins Hyper IgE Hyper IgM Syndrome AIDS
B-Cell Defects
Agamma-globulinemia
B cell
0-2 %
IgG 100 mg/dl
IgA 0-10 mg/dl
IgM 0-20
Transient Hypogamma-
Globulinemia of infancy(THI)
B cell
10-20 %
IgG 250 mg/dl
IgA 10 mg/dl
IgM 20 mg/dl
Common variable immune deficiency
(CVID)
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+,CD56T Lymphocyte proliferation test
Timus X ray
SCIDLymphopenia ( < 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 hypersensitivityAdvanced 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+
T+B+
Adenosine deaminase deficiency
Reticular dysgenesis
RAG 1 /2
deficiency
Omenn syndrome
Navajo
SCID
X-SCIDJAK3 deficiency
PNP deficiency
IL-7 Rdeficiency
CD3deficiency
ZAP-70 deficiency
Tip2 BLSIL-2 deficiency
IgG - - - - ±
- N -
IgA - - - - ±
- N + ±
IgM - - - ±
N, , +
IgE - - - - - N -
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, morphologyAdvanced 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
Nitroblue tetrazolium(NBT) testSuperoxide 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
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 Tests1.CH50 (total hemolytic complement activity)
2.AH50 (alternative pathway hemolytic activity)
Advanced Tests1.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
OtherAdvanced 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