Primary Immune Deficiencies (PIDs)

• Definition- Genetic defects that affect development and/or function of the immune system- Over 130 distinct forms of PIDs are known (IUIS PIDs Classification, 2007)

• Incidence- 1/10,000, but higher in areas with increased consanguinity- Recent data suggest that incidence of PIDs may be much higher than previously anticipated (susceptibility to severe infections).

Primary Immune Deficiencies (PIDs):importance and social impact

• Importance- increased susceptibility to: - severe and recurrent infections - malignancy - autoimmunity

• Social impact- high mortality and morbidity rate- development of multiorgan chronic complications- costly use of health care resources

Accurate diagnosis is essential for proper treatmentand for genetic counseling

antibody deficiencies(55.4%)combined immunodeficiencies

(10.6%)

innate immunity defects(13%)

complement defects(1.8%)

Immunodysregulation disorders (1.2%)

Complex PID syndromes(18%)

The distribution of PIDs*

*data on 6,020 patients with PID. ESID, 2008

PIDs in the Middle East: special considerations

• higher prevalence rate (consanguinity)

• delayed recognition

• inadequate support to provide molecular diagnosis

• difficulties in providing optimal treatment

PIDs represent a significant Public Health issue for Middle East countries

PIDs in the Middle East: Opportunities for research

Increased number of patients with autosomal recessive PIDs

Patients withunique phenotypes

Identification of novel PID genes

Novel PID genes identified throughthe study of patients from the Middle East

• Ataxia-telangiectasia• CD40L deficiency• CD40 deficiency• AID deficiency• SCID due to JAK3 deficiency• heavy chain defect• Ig chain deficiency• VODI (veno-occlusive disease with immunodef.)• Familial mycobacteriosis due to defects in the

IL-12/IL-12R/INF-/INF-R/STAT1 axis • HLH due to syntaxin 11 deficiency

Partnership

• Raif S. Geha, Luigi D. Notarangelo Division of Immunology, Children’s Hospital, Boston

• Basel Ramadi and Suleiman Alhammadi Faculty of Medicine, UAE University, Al-Ain, UAE

• Waleed Al-Herz Al-Sabah Hospital, Kuwait

• Ghassan Dbaibo American University of Beirut Medical Center, Lebanon

• Abdullah Alangari King Khalid University Hospital, Saudi Arabia

• Necil Kutukculer Ege University, Izmir, Turkey

Facilities / programs available at our centerAvailability (no / year 2007)

I. Clinical diagnosis

In-patient service for PID 264 / year (28% new dx)

Outpatient service for PID 1466

II. Laboratory diagnosis

Phenotyping 600 (incl. lymphocyte phenoyping, differentiation patterns, 63 for leukemia)

Functional assays

- humoral √ ( anti-tetanus-antiHIB-differentiation studies)

- cellular √ (in vitro l. prol.)

- innate Burst test

Molecular diagnosis √ (in the same building, different lab)

III. Treatment

IVIG √

Bone marrow transplantation √ (6 for PID in 2007)

IV. Training program in PID √ (pediatric immunology fellowship+ medical students from year 2 to 6)

Estimated number of patients with various forms of PID followed at our center

Estimated numberof patients

Antibody deficiencies 410

Cellular immune deficiencies (incl.SCID+combined)

50

Innate/phagocytic cell defects 40

Immune deficiency syndromes 60

DIVISION CHIEF - RAIF S. GEHA

ADMINISTRATION 1 Admin. Manager

1 Financial Manager 4 AA.

CLINICAL PROGRAMHANS OETTGEN

1 Clinic Practice manager4 RN, 5 AA

LABORATORY PROGRAM

RHEUMATOLOGYROB SUNDEL3 F.T. STAFF4 P.T. STAFF

1 AA

ALLERGYLYNDA SCHNEIDER

4 F.T. STAFF8 P.T. STAFF

1 AA

DERMATOLOGYSTEVE GELLIS2 F.T. STAFF3 P.T. STAFF

1 AA CLINICAL RESEARCHLYNDA SCHNEIDER

1 Res Coordinator2 CLINICAL ASST.

LAB RESEARCH

DXTIC LABT. BONILLA

2 TECHS

TRAINING PROGRAMHans Oettgen

10 CLINICAL FELLOWS1 AA

CL. IMMUNOL.Tony Bonilla3 F.T. STAFF

1 AA

Geha3 junior staff

10 fellows1 tech1 AA

Notarangelo2 junior staff

5 fellows1 tech1 AA

Umetsu2 junior staff

10 fellows2 tech1 AA

Oettgen4 fellows

1 tech

The operating budget for 2007 was $ 17,671,994: $ 7,864,313 for research and $9,807,681 for clinical operations.

CLINICAL

AllergyImmunodeficiency

RheumatologyDermatology

TRAINING

CLINICAL RESEARCH

BASIC RESEARCH8 physician scientists

11 basic scientists

12 current investigators

DIAGNOSTIC

12 full timers15 part timers

5 investigators

Programs in the Division of Immunology at CH

2 Assoc. Professors 3 Professors

3 PhD in other HMS labs

IMMUNOLOGY

FACS analysis Functional studies Molecular Dx.

PROGRAMS

PROGRAM

7 Assist. Professors

Outreach of the Division of Immunology, CHB

• Harvard Medical School- Course in Primary Immune Deficiencies- Two ongoing Program Project grants- Graduate students (PhD thesis work on PID)

• National- USIDNET- Jeffrey Modell Center for Immunodeficiency- FOCIS Center of Excellence in Pediatric Immunology- NIH T32 training grant for fellows in Allergy/Immunology

• International- PID Committee, International Union of Immunological Societies

(Chairs: Raif S. Geha, Luigi D. Notarangelo)

Specific Aims

I. Identify the cellular and molecular basis of well characterized, but genetically undefined, PIDs

II. Identify the molecular and cellular bases underlying novel PIDs

III. Determine the incidence, genotype-phenotype correlation, and natural history of PIDs in the Middle East

Strategic plan to reach our goals

• Sharing of standards for Quality Control purpose.

• Sharing of reagents not commercially available (antibodies, cell lines).

• On-site visits of senior technicians and post-docs to help set up novel diagnostic tests.

Implementation of diagnosis in the Middle East

Strategic plan to reach our goals

• Establish genotype-phenotype correlations specific to well defined PIDS

• Identify patients with undefined PIDs

• Take advantage of expertise and high-tech tools available in Boston to unravel the molecular defects in novel PIDs

Research

Strategic plan to reach our goals

• Bidirectional visits with partners (1-2 visits per year)

• Short-term (2-3 months) training opportunities at CHB.

• On-site clinical training in the Middle East.

Training

Strategic plan to reach our goals

• Bimonthly conference calls. • Invite Middle East partners to:

- bi-yearly IUIS Workshop on PIDs

- yearly meeting of the PID Center in Boston

Communication and integration process

• Co-authorship of scientific publications