1. ANGEBORENE UND ERWORBENE IMMUNDEFIZIENZEN: VOM KLINISCHEN BILD ZUR MOLEKULAREN PATHOLOGIE CONGENITAL AND ACQUIRED IMMUNODEFICIENCIES: FROM CLINICAL PHENOMENON TO MOLECULAR PATHOLOGY J. Lokaj Universitätskrankenhaus St. Anna, Brünn / CZ Abteilung für klinische Immunologie und Allergologie Immunologische Laboratorien Prof. Ringel, Aachen / D

2. Genome Immune System Endocrine System Nervous System HOMEOSTASIS Environmental and lifestyle factors

3. non self altered self missing self danger/alarm signals IMMUNE REACTIVITY Complement system Histamine Antimicrobial peptides Interferons Acute phase reactans Cytokines Immunoglobulins Lymphocytes B Lymphocytes T NK, NKT cells Antigen presenting cells Professional phagocytes Mastocytes Endothelial cells Epithelial cells ELIMINATION PROTECTION MEMORY TOLERANCE PARALYSIS PATHOLOGY

4. non self altered self missing self danger/alarm signals IMMUNE REACTIVITY Complement system Histamine Antimicrobial peptides Interferons Acute phase reactans Cytokines Immunoglobulins Lymphocytes B Lymphocytes T NK, NKT cells Antigen presenting cells Professional phagocytes Mastocytes Endothelial cells Epithelial cells ELIMINATION PROTECTION MEMORY TOLERANCE PARALYSIS PATHOLOGY

5. The innate immune system evolved several strategies of self/nonself discrimination that are based on the recognition of molecular patterns demarcating infections nonself, as well as normal and abnormal self. These patterns are deciphered by receptors that either induce or inhibit an immune response, depending on the meaning of these signals. Ruslan Medzhitov, Charles A. Janeway Jr.: Decoding the Pattern of Self and Nonself by the Innate Immune System (Science 2002; 296: 298-300)

6. The immune system is more concerned with entities that do damage than those that are foreign. Poly Matzinger: The Danger Model: A Renewed Sense of Self (Science 2002; 296: 301-305)

7. Disorders of the Immune System HYPO- FUNCTION DYS- FUNCTION TUMORS OF THE IMMUNE SYSTEM IMMUNO- DEFICIENCY ALLERGY AUTOIMMUNITY HYPER- FUNCTION

8. Increased susceptibility to infections Proneness to malignancy Autoimmunity Dysregulation in immune networks IMMUNODEFICIENCY PRIMARY (CONGENITAL) SECONDARY (ACQUIRED)

9. The time course of infections in immunodeficient hosts Deficiency of innate immunity Deficiency of adaptive immunity Immunocompetent host

10. Warning Signs of Primary Immune Deficiency Eight or more new ear infections within 1 year. Two or more serious sinus infections within 1 year. Recurrent, deep skin or organ abscesses. Persistent thrush in mounth or elselwhere on skin, after age 1. Need for intravenous antibiotics to clear infections. Two or more deep-seated infections such as meningitis, osteomyelitis, cellulitis, or sepsis. A family history of primary immunodeficiency. Two or more months on antibiotics with little effect. Two or more pneumonias within 1 year. Failure of an infant to gain weight or grow normally.

11. Bruton CO: Agammaglobulinemia Pdiatrics 1952; 9: 722-727 Glanzmann E, Riniker P: Essentielle Lymphocytophtise: Ein neues Krankheitsbild aus der Säuglingspathologie Ann Pediatr (Basel) 1950; 174: 1-5 Good RA: Experiments of nature in immunobiology. N Engl J Med. 1968; 279: 1344-5 PRIMARY IMMUNODEFICIENCY: PROLOGUE

12. EUROPEAN SOCIETY FOR IMMUNODEFICIENCIE (ESID) ESID REGISTRY OF PRIMARY IMMUNODEFICIENCIES (2002, Population: 666 137 163) 9707 patients Prevalence: 1,46/100 000 Antibody deficiencies 66,3% T-cell or combined deficiencies 17,6% Phagocytic disorders 7,4% Complement deficiencies 6,2% other Primary Immunodeficiencies 2,5%

13. CZECH NATIONAL REGISTRY OF PRIMARY IMMUNODEFICIENCIES (Inhabitans: cca 10 100 000, patients: 548, 31. 12. 2002) COMBINED DEFICIENCIES n M F age % __________________________________________________________ SCID (D81.9) 8 7 1 1-8 1,46 DIGEORGE ANOMALY (D82.1) 26 10 16 1-19 4,7 WISKOTT-ALDRICH SYNDROME 3 3 - 5-30 0,55 (D82.0) ATAXIA TELEANGIECTASIA (G11.3) 2 1 1 6-11 0,37 CHRON. MUCOCUT. CANDIDIASIS 2 1 1 31-46 0,37 (B37.9)

14. CZECH NATIONAL REGISTRY OF PRIMARY IMMUNODEFICIENCIES (Inhabitans: cca 10 100 000, patients: 548, 31. 12. 2002) ANTIBODY DEFICIENCIES n M F age % __________________________________________________________ IgA DEFICIENCY (D80.2) 283 134 149 5-80 51,64 COMMON VARIABLE 102 51 51 7-84 18,61 IMMUNODEFICIENCY, CVID (D83.9) AGAMMAGLOBULINEMIA 22 22 - 8-50 4,01 X-LINKED, X-LA (D80.0) IgG SUBCLASS DEFICIENCY (D80.3) 13 1 12 11-62 2,37 HYPER IgM SYNDROME (D80.5) 4 2 2 11-27 0,73

15. CZECH NATIONAL REGISTRY OF PRIMARY IMMUNODEFICIENCIES (Inhabitans: cca 10 100 000, patients: 548, 31. 12. 2002) PHAGOCYTIC DISORDERS n M F age % __________________________________________________________ CHRONIC GRANULOMATOUS 10 4 6 8-41 1,82 DISEASE, CGD (D71) LEUKOCYTE ADHESION DEFECT, 1 1 0 13 0,19 LAD (D84.0)

16. CZECH NATIONAL REGISTRY OF PRIMARY IMMUNODEFICIENCIES (Inhabitans: cca 10 100 000, patients: 548, 31. 12. 2002) COMPLEMENT DEFICIENCIES n M F age % __________________________________________________________ C1 ESTERASE INHIBITOR 58 24 34 10-84 10,58 DEFICIENCY (D84.1) C2 DEFICIENCY (D84.8) 2 1 1 3-7 0,37 C4 DEFICIENCY (D84.8) 3 0 3 7-51 0,55

17. CZECH NATIONAL REGISTRY OF PRIMARY IMMUNODEFICIENCIES (Inhabitans: cca 10 100 000, patients: 548, 31. 12. 2002) OTHER PRIMARY n M F age % IMMUNODEFICIENCIES __________________________________________________________ HYPER IGE SYNDROME 7 5 2 10-39 1,27 (D82.4) X-LINKED LYMPHOPROLIFERATIVE 2 2 - 0,37 SYNDROME, X-LP

18. The prevalence of immunodeficiency disorders in Europe (2003) 577 577 10193 10193 5,5

19. The critical components of an immune response

20. Mechanisms underlying primary immunodeficiencies Lymphocyte development Severe combined immunodeficiencies X-linked agammaglobulinemia DiGeorge syndrome DNA repair Ataxia telangiectasia Nijmegen breakage syndrome Bloom syndrome Lymphocyte apoptosis IL2Rα deficiency Autoimmune lymphoproliferative syndrome Cytolytic pathway (low NK and CTL activity) Lymphohistiocytosis Griscelli syndrome Chediak-Higashi syndrome Haemophagocytic syndrome (macrophage activation syndrome)

21. Mechanisms underlying primary immunodeficiencies Antigen presentation HLA class II deficiencies TAP 1 / 2 deficiencies Immunoglobulin class switch recombination HyperIgM syndrome I and II Cell migration Wiskott-Aldrich syndrome Leucocyte adhesion deciency Activation of intracellular pathogen killing pathway Susceptibility to ycobacterial infections Activation of extracellular pathogen killing pathway Susceptibility to pyogenic bacteria Killing of pathogens through the oxidative burst Chronic granulomatous diseases

22. PRIMARY IMMUNODECIENCIES ARE GENETIC DISEASES One syndrome, several genes HLA class II deficiency (CIITA, RFX-5, RFX-AP, RFX-ANK) Autosomal recessive agammaglobulinemia (µ, λ5, Igα) Autosomal recessive chronic granulomatous disease (p22, p47, p67) Susceptibility to mycobacterial infections (IFNγRI, IL2p40, IL2Rβ1/β2) One gene, several syndromes RAG-1/RAG-2 (B-SCID, Omenn syndrome) WASP (Wiskott-Aldrich syndrome, X-linked thrombocytopenia) BTK (agammaglobulinemia, hypogammaglobulinemia) Modifier genes and environmental factors could influence the expression pattern of immunodeficiency

23. Risk for malignant lymphoma and stomach cancer

26. Common variable immunodeficiency (CVID) unimpaired antigen presentation defective integration of activating signals in both CD4 + and CD8 + lymphocytes lymph node B cells are able to produce IgG

29. Interleukins IgIg ANTIG EN

33. Conclusion The impairment of TCR-mediated signalling leading to reduced cytokine production and decreased expression of CD40L is likely to contribute to the hypogammaglobulinemia in a significant subset of CVID patients.

36. Lekstrom-Himes, JA, Gallin, JI: New Engl J Med 2000; 343: 1703-1714

37. Chronic Granulomatous Disease (X-linked)

38. Chronic Granulomatous Disease (autosomal recessive)

39. more common than primary immunodeficiencies occur in many hospitalized patients (immunocompromised host, critically ill patient) often reversible if the underlying conditions resolve predisposing factors: infection, malnutrition, malignancy, systemic disorders, severe trauma, alteration in the endocrine and/or nervous systems, cytotoxic chemoradiotherapy, immunosuppression consequences: increased susceptibility to infectious agents proneness to malignancy imbalance in immune networks ACQUIRED (SECONDARY) IMMUNODEFICIENCIES

40. The time course of infections in immunodeficient hosts Deficiency of innate immunity Deficiency of adaptive immunity Immunocompetent host

42. The future of immunology will be all about how the system is regulated and how it makes decisions: whether to direct efforts towards antibody formation or cell-mediated immunity, and, if the latter, whether more towards cytokine secreting T cells or cytotoxic cells. Gustav J. V. Nossal: The double helix and immunology (Nature 2003; 421: 440-444)