Congenital and acquire Immunodeficiency

1. Congenital and acquire Immunodeficiency Wei Chen, Associate professor Institute of Immunology E-mail:chenwei566@zju.edu.cn http://mypage.zju.edu.cn/566 8888

2. Objectives • 􀁺 To understand the concept of immunodeficiency. • To know the main types of primary immunodeficiency diseases. • 􀁺 Be able to describe characteristics and consequence of HIV infection.

3. Content • Introduction • Primary immunodeficiency diseases • Secondary immunodeficiency diseases

4. Immunodeficiency • Defects in the development and functions of the immune system. • Result in increased susceptibility to infections and in an increased incidence of certain cancers. • Disorders caused by defective immunity are called immunodeficiency diseases.

5. General feature of immunodeficiency diseases • The principal consequence of immunodeficiency is an increased susceptibility to infection. • Patients with immunodeficiencies are also susceptible to certain types of cancer. • Paradoxically, certain immunodeficiencies are associated with an increased incidence of autoimmunity. • Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity.

6. Classification • Primary or congenital immunodeficiencies • Present at birth • Result from genetic abnormalities in one or more components of the immune system • Secondary or acquired immunodeficiencies • Later in life • Result from infections, malnutrition, or treatments that cause loss or inadequate function of various components of the immune system • Most common is acquired immunodeficiency syndrome, or AIDS

7. Content • Introduction • Primary immunodeficiency diseases • Secondary immunodeficiency diseases

8. Primary immunodeficiency diseases • Severe Combined Immunodeficiencies (SCID) • Antibody Deficiencies: Defects in B Cell Development and Activation • Defects in T Lymphocyte Activation and Function • Defects in Innate Immunity • Multisystem Disorders with immunodeficiency

9. Features of immunodeficiency diseases

10. congenital immunodeficiencies caused by defects in lymphocyte maturation

11. Severe Combined Immunodeficiency Syndromes (SCID) • Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies. • characterized by deficiencies of both B and T cells or only of T cells; in the latter cases, the defect in humoral immunity is due to the absence of T cell help. • Children with SCID usually have infections during the first year of life.

12. Severe Combined Immunodeficiency Syndromes (SCID) • Athymic - DiGeorge Syndrome • X-linked SCID (c deficiency) • Adenosine deaminase deficiency (腺苷脱氨酶) • Jak3 kinase deficiency • Purine nucleoside phosphorylase deficiency • Bare lymphocyte syndrome • RAG1 and RAG2 deficiency

13. Precursor T cell differentiation defect • Athymic - DiGeorge Syndrome • Sporadic microdeletion of 22q, TBX1 gene (T-box1) • Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and T regulatory (Treg) cells • B cells are present but T-dependent B cell responses are defective • Anti-viral and anti-fungal immunity impaired • Developmental defect in the 3rd and 4th pharyngeal pouch • Results in facial defect and congenital heart disease

14. DiGeorge syndrome

15. X-Linked SCID: Common Cytokine Receptor Gamma Chain (gc) Deficiency • Most common form of SCID (40%) • Responsible gene: γc– the common subunit of receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 • Very low T cells and NK cells with low to normal numbers of B cells

17. Nude Athymic mouse • FOXN1 gene knock-out (autosomal recessive) • Hairless • Should be maintained in pathogen-free environment • T helper cell defect • Results in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defect • Accept xenografts

18. Antibody Deficiencies: Defects in B Cell Development and Activation • Bruton’s (X-linked) Agammaglobulinemia • Common Variable Immunodeficiency (CVID) • Autosomal Recessive Hyper-IgM Syndrome • B Cell Receptor Deficiencies • Selective IgA Deficiency • IgG Subclass Deficiency

19. XLA - BTK defect • Defect in B cell maturation • Genetic disorder - gene on X-chromosome • codes for Bruton’s tyrosine kinase - BTK essential for B cell development

20. Essential role of BTK

21. Bruton’s X-linked Agammaglobulinemia • The absence of B cells in blood and IgG • x-linked recessive inheritance, males • Child clinically well for first 6 months of life • Recurrent upper/lower respiratory tract infections with encapsulated bacteria • Sepsis (败血症), meningitis (脑膜炎), skin infections • Paucity of lymphoid tissue (tonsils, adenoids) • Treatment: inject pooled gamma globulin preparations

22. Common Variable Immunodeficiency • Panhypogammaglobulinemia (全丙种球蛋白过少血症), usually with lymphadenopathy and splenomegaly • Absence of clear abnormalities in T and B cell subsets • Chronic/recurrent respiratory infections, diarrhea(腹泻) • Tendency to develop autoimmunity and lymphoid malignancies • Linkage to HLA Class III Region in 2/3 of patients • One gene identified: ICOS (B7h) (activation antigen on T cells)

23. Defects in Innate Immunity • Phagocyte Deficiencies: • Chronic granulomatous disease (CGD) • Leukocyte adhesion deficiency (LAD I) • Complement Deficiency • Defects in NK cells and other leukocytes: the Chédiak-Higashi syndrome • Inherited defects in TLR Pathways, NF-κB signaling and type I Interferons • IL-12/IFN pathway deficiencies

24. Congenital immunodeficiencies caused by defects in innate immunity

25. Chronic Granulomatous Disease • Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase • Severe tissue infections with catalase positive organisms, esp. Staph aureus, Serratia marcescens, mycobacteria, and fungi such as Aspergillus

27. Chronic granulomatous disease • Note cervical nodal abscess(头颈淋巴结脓肿) • Gingivitis and periodontitis (牙龈炎和牙周炎) • Abscess indenting the oesophagus(食道脓肿)

28. CGD patient with skin infections due to Serratia marcescens

29. Content • Introduction • Primary immunodeficiency diseases • Secondary immunodeficiency diseases

30. Secondary or acquired immunodeficiency diseases

31. Human Immunodeficiency Virus • Discovered in 1983 by Luc Montagnier and Robert Gallo • Retrovirus (RNA virus) • HIV-1 (common) and HIV-2 (Africa) • Patients with low CD4+ T cells • Virus prevalent in homosexual, promiscuous heterosexual, i.v. drug users, transfusion, infants born to infected mothers • Opportunistic infections with Pnuemocystis carinii (卡氏肺囊虫), Candida albicans, Mycobacterium avium, etc. • Patients with HIV have high incidence of cancers such as Kaposi sarcoma

32. Kaposi Sarcoma

33. Incidence of HIV CDC 2008

34. HIV - The Virus • A retrovirus • Genetic material is RNA • Transcribed into DNA by RT (reverse transcriptase) • Copy (provirus) inserted into the host genome • When it is expressed to form new virions, the cell lyses • Alternately, it may remain latent in the cell for an extended period of time

35. The structure of human HIV-1

36. Genes of human HIV-1

37. The life cycle of HIV-1 • Infection of cells: gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M. • Production of viral DNA and its integration into the host genome. • Expression of viral genes: production of viral RNAs and then proteins to form a core structure. • Production of viral particles: the core structure migrates to the cell membrane, acquires a lipid envelope from the host, and the viral particle is shed.

38. The life cycle of HIV-1

39. Pathogenesis of AIDS • HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus. This viral production leads to death of infected cells and uninfected lymphocytes, subsequent immunodeficiencies and clinical AIDS. • The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus, resulting from production of viral particles, as well as death of uninfected cells.

40. Course of AIDS Dissemination of virus; Seeding of lymphoid organs Anti-HIV Ab/CTL ACUTE CHRONIC AIDS PHASE PHASE AIDS (<200cells/mm3)

41. The pathogenesis of AIDS

42. The earliest innate and adaptive immune responses detected after HIV transmission Nat Rev Immunol. 2010,10:11

43. Animal Models • Primate Model: • HIV grows in chimpanzees but do not develop AIDS • Simian immunodeficiency virus (SIVagm in African green monkey – no disease; SIVmac in Macaques – AIDS like); • Mouse Model: • Grows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes

44. US Death Rates 25-44 years old

45. Therapy and vaccination strategies • Several places in virus life-cycle that can be blocked • Attachment/entry • Reverse transcription • Integration • Proteolysis

47. Reverse Transcription • AZT (zidovudine) • Nucleoside analog - is incorporated into growing chain and causes termination • Side effects • Resistant mutants develop • Nevirapine • Inhibits action of RT

50. Protease Inhibitors • Blocks action of protease • Huge breakthrough! • Responsible for rapid drop in number of deaths in US