Primary Immune Deficiencies (PIDs)

1. 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).

4. 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 treatment and for genetic counseling

5. The distribution of PIDs* Complex PID syndromes (18%) Immunodysregulation disorders (1.2%) complement defects (1.8%) innate immunity defects (13%) antibody deficiencies (55.4%) combined immunodeficiencies (10.6%) *data on 6,020 patients with PID. ESID, 2008

6. 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

7. PIDs in the Middle East: Opportunities for research Increased number of patients with autosomal recessive PIDs Patients with unique phenotypes Identification of novel PID genes

8. Novel PID genes identified through the study of patients from the Middle East • Ataxia-telangiectasia • CD40L deficiency • CD40 deficiency • AID deficiency • SCID due to JAK3 deficiency •  heavy chain defect • Iga 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

9. 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

11. Facilities / programs available at our center

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

13. DIVISION CHIEF - RAIF S. GEHA CLINICAL PROGRAM HANS OETTGEN 1 Clinic Practice manager 4 RN, 5 AA ADMINISTRATION 1 Admin. Manager 1 Financial Manager 4 AA. LABORATORY PROGRAM DXTIC LAB T. BONILLA 2 TECHS LAB RESEARCH ALLERGY LYNDA SCHNEIDER 4 F.T. STAFF 8 P.T. STAFF 1 AA CL. IMMUNOL. Tony Bonilla 3 F.T. STAFF 1 AA TRAINING PROGRAM Hans Oettgen 10 CLINICAL FELLOWS 1 AA RHEUMATOLOGY ROB SUNDEL 3 F.T. STAFF 4 P.T. STAFF 1 AA DERMATOLOGY STEVE GELLIS 2 F.T. STAFF 3 P.T. STAFF 1 AA Geha 3 junior staff 10 fellows 1 tech 1 AA Notarangelo 2 junior staff 5 fellows 1 tech 1 AA CLINICAL RESEARCH LYNDA SCHNEIDER 1 Res Coordinator 2 CLINICAL ASST. Umetsu 2 junior staff 10 fellows 2 tech 1 AA Oettgen 4 fellows 1 tech The operating budget for 2007 was $ 17,671,994: $ 7,864,313 for research and $9,807,681 for clinical operations.

14. Programs in the Division of Immunology at CH TRAINING PROGRAM CLINICAL PROGRAMS 8 physician scientists 11 basic scientists BASIC RESEARCH Allergy 3 PhD in other HMS labs Immunodeficiency 12 current investigators Rheumatology 3 Professors Dermatology 2 Assoc. Professors 7 Assist. Professors 12 full timers 15 part timers CLINICAL RESEARCH 5 investigators DIAGNOSTIC IMMUNOLOGY FACS analysis Functional studies Molecular Dx.

15. 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)

16. Specific Aims • Identify the cellular and molecular basis of well • characterized, but genetically undefined, PIDs • Identify the molecular and cellular bases • underlying novel PIDs • Determine the incidence, genotype-phenotype correlation, and natural history of PIDs in the Middle East

17. Strategic plan to reach our goals Implementation of diagnosis in the Middle East • 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.

18. Strategic plan to reach our goals Research • 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

19. Strategic plan to reach our goals Training • 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.

20. Strategic plan to reach our goals Communication and integration process • Bimonthly conference calls. • Invite Middle East partners to: • - bi-yearly IUIS Workshop on PIDs • - yearly meeting of the PID Center in Boston • Co-authorship of scientific publications