1. Congenital and acquire Immunodeficiency
Wei Chen, Associate professor Institute of Immunology

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)
Left. Molecules involved in oxidase burst activity
Right. Clinical lesions found in CGD - lymphadenopathy and gingivitis

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 Anti-HIV Ab/CTL ACUTE CHRONIC 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: Mouse 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

51. Combination Therapy HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15,000/yr)

52. Therapies
Ongoing work to develop drugs to interfere with integration and with attachment/entry
Takes many years to pass tests for safety and efficacy

53. Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies, but they don’t protect