Immunology

1. Chapter 18 AIDS and other Immunodeficiences Dr. Capers Immunology

2. Autoimmunity – system attacks host cells and tissues • Immunodeficiency – system fails to protect • Primary immunodeficiency • Genetic or developmental defect • Secondary immunodeficiency - acquired

3. Primary ImmunodeficienciesLymphoid Immunodeficiences • Combined – effects both B and T cells • B-cell Immunodeficiency • Range from absence of B cells, plasma cells, immunoglobulins to absence of only certain classes of Abs • Subject to bacterial infections but do well against viral since T-cell branch is ok • T-cell Immunodeficiency • Can effect both humoral and cell-mediated

8. Primary immunodeficiences are often detected early in life

9. Primary ImmunodeficiencesCombined Immunodeficiences • Severe Combined Immunodeficiency (SCID) • Low # of circulating lymphocytes • Non-proliferating T cells • Thymus doesn’t develop • Usually fatal early years of life • Infant will have viral and fungal infections • Bacterial don’t show up until later because of placental transfer of Abs from mother • Chronic diarrhea, pneumonia, lesions • Many genetic defects can contribute to SCID • Usually defects that target the early steps of hematopoiesis

10. Primary ImmundeficienciesCombined Immunodeficiencies • MHC defects • Symptoms can resemble SCID • Bare-lymphocyte syndrome • Failure to train T cells correctly, it effects both B and T cells

11. Primary ImmunodeficienciesCombined Immunodeficiencies • Thymus • DiGeorge Syndrome – decreased or absent thymus • Results from deletion of region on chromosome 22 in developing embryo, developmental anomaly • Lowered T cell numbers, results in B cells not producing sufficient Abs

12. Primary ImmunodeficiencesCombined Immunodeficiences • Wiskott-Aldrich Syndrom (WAS) • X-linked disorder • Results in issues with cytoskeleton components in hematopoietic cells • Initially B and T cell numbers are normal but will decrease with age • Treated with passive antibodies or stem cell transfer • can result in fatal infection or lymphoid malignancy

13. Primary ImmunodeficiencesCombined Immunodeficiences • X-linked Hyper-IgM Syndrome • Deficiency of IgG, IgE, IgA but elevated levels of IgM • Defect in T cell surface marker CD40L • This is needed for interaction between TH and B cell for class switching for T-dependent antigens • T independent antigens are not effected therefore there is production of IgM

14. Primary ImmunodeficiencesCombined Immunodeficiences • Hyper-IgE Syndrome (job syndrome) • Autosomal dominant • Skin abscesses, pneumonia, eczema, facial abnormalities • High # of eosinophils and IgE • But don’t show increased allergies

15. Primary ImmunodeficiencesB cell Immunodeficiences • X-linked Agammaglobulinemia • B cell defect • Defect in kinase that keeps B cells in pre-B stage with H chains rearranged but L chains not • Low levels of IgG and absence of other classes • Recurrent bacterial infections

16. Primary ImmunodeficiencesB cell Immunodeficiences • Common Variable Immunodeficiency (CVI) • Low levels of immunoglobulin – hypogammaglobulinemia • Manifests later in life • Undefined genetic component

17. Primary ImmunodeficiencesB cell Immunodeficiences • Selective Deficiences of Immunoglobulin Classes • IgA deficiency is most common • Recurrent respiratory and urinary tract infections, intestinal problems

18. Primary ImmunodeficienciesInnate Immunodeficiencies • Leukocyte Adhesion Deficiency (LAD) • Integrin proteins needed for adhesion and cellular interaction • Defect limits recruitment of cells into areas of inflammation

19. Primary ImmunodeficienciesInnate Immunodeficiencies • Chediak-Higashi Syndrome • Autosomal recessive disease • Phagocytes don’t have ability to kill bacteria • Issue with lysosome activity

20. Primary ImmunodeficiencesInnate Immunodeficiences • Interferon-Gamma-Receptor Defect • Autosomal recessive trait – results from inbreeding • Defect in receptor for IFN-γ and subsequent pathways • Patients suffer from infection with mycobaterium, showing importance of this receptor in fighting mycobacterium

21. Primary ImmunodeficienciesMyeloid Immunodeficiencies • Reduction in neutrophil count • Low concentration – granulocytopenia or neutropenia • Congenital neutropenia • Frequent bacterial infections • Acquired neutropenia • Certain drugs or chemotherapy can cause this • Autoimmune disorder – destruction of neutrophils

22. Primary ImmunodeficienciesInnate Immunodeficiencies • Complement deficiencies • Fairly common • Mostly associated with bacterial infections or immune-complex diseases

23. Treatments for Immunodeficiency • Replacement of missing protein • Administering immunoglobulin • Express genes in vitro (in bacteria) for cytokines • Replacement of missing cell type • Bone marrow transplantation • Replacement of missing or defective gene • Gene therapy • Still far out from clinical use • Can it be corrected in vitro and then introduce cells back into patient? • Watch this video on CRISPR/cas9: https://www.youtube.com/watch?v=2pp17E4E-O8&index=6&list=PLtnoha_whQGLjpUEIuchj3f7lW2NYNj4r

24. Animal Models • Nude mouse • Genetic mutation (Nu, now called Foxn1nu) • No hair • Vestigal thymus – No T cells • Die early from opportunistic pathogens, must use great care when used in research • What are they used for? • They can tolerate allografts and xenografts • Cancers can be grown in them – allowing propagation and evaluation of drugs and imaging techniques to be researched

25. SCID Mouse • Genetic mutation (PRKDC) • Defective Ig and TCR gene rearrangement • “leaky” – can have some functioning B and T cells

26. RAG Knockout mice • RAG1/RAG2 genes mutated • No B, T or NK cells • Can reconstitute these mice with “immune system” of another animal to test disease progression and treatments

27. Now we will talk about Secondary (Acquired) Immunodeficienceies

28. Acquired Immunodeficencies • No genetic component • Examples: • Hypogammaglobulinemia – unknown cause, different from genetic condition • AIDS caused by HIV • Watch this video : https://www.youtube.com/watch?v=5g1ijpBI6Dk

29. AIDS and other secondary acquired Immunodeficiences

30. HIV • Retrovirus (Lentavirus genus) • Viral envelope derives from host • Can have Class I and Class II MHC • Recognizes CD4 antigen on T cell

31. HIV-1 – main causative agent for AIDS • Many different subtypes • Probably evolved from SIV and transferred to humans during the “bushmeat trade” in early 1900s • HIV-2 – cousin to HIV-1 but disease progresses slowly, if at all

33. Passage of HIV (green) between T cell and dendritic cell

34. HIV Treatment

35. Vaccine may be only Way to stop HIV