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