Immunodeficiency syndromes part 3
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T cell deficiencies, combined B- and T-cell immunodeficiency, acquired immunodeficiency disease and diseases of immune dysregulation.
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Immunodeficiency syndromes part 3
- 1. Immunodeficiency Syndromes Part Three T cell Deficiencies, Combined B- and T-cell Immunodeficiency, Acquired Immunodeficiency Disease and diseases of Immune Dysregulation April 23, 2013 Roy C. Maynard, M.D.
- 2. Review – Part Two Deficiencies of innate immune system and other well-defined immunodeficiency syndrome January 23, 2013 2
- 3. Conclusions – Part Two • Immunodeficiency disorders are fairly infrequent • Some are transient with improvement over time • More severe forms of immunodeficiency are associated with shortened life span without bone marrow transplantation • A genetic cause has been identified for a substantial portion of these disorders 3
- 4. Conclusions – Part Two • Treatment options include: – Prophylactic antibiotics – SQ gammaglobulin – IV gammaglobulin – Stem cell or bone marrow transplantation – New biologicals – Gene therapy 4
- 5. Immunodeficiency Syndromes Part Three T cell Deficiencies Combined B- and T-cell Immunodeficiency Acquired Immunodeficiency Disease Diseases of Immune Dysregulation 5
- 6. Objectives • Understand aspects of the immune system affected in severe combined immunodeficiency disease • Identify some of the features of Hemophagocytic Lymphohistiocytosis (HLH) • Describe how retroviruses replicate in HIV disease
- 7. Objectives • Primary T-cell defect – DiGeorge syndrome – X-linked hyperIgM syndrome • T and B cell defect – SCID • Disorders of Immune Dysregulation – HLH – X-linked lymphoproliferative syndrome • HIV
- 8. DiGeorge Syndrome • Clinical Presentation – Newborn period – Heart defect – Abnormal facies – Cleft palate – Seizures – 3rd and 4th pharyngeal pouches
- 9. DiGeorge Syndrome http://medicalanomalies.blogspot.com/2012/09/digeorge-syndrome.html Accessed on 4/22/13
- 10. DiGeorge Syndrome http://classconnection.s3.amazonaws.com/1602/flashcards/688010/jpg/pharyngeal-pouches.jpg Accessed on 4/22/13 - Images
- 11. DiGeorge Syndrome • Laboratory – Hypocalcemia – Hypoparathyroidism – Absent thymus on CXR – Decreased circulating T-cells – Decreased T-cell response – Deletion long arm chromosome 22 – Primarily a T-cell defect
- 12. X-linked Hyper IgM Syndrome • Males – 2 per million • CD40L deficiency • CD40L is on surface of activated T-cells • Activated T-cells use CD40L to interact with B cells to switch from IgM production to IgG production • Increased IgM, decreased IgG
- 13. Severe Combined Immunodeficiency Disease (SCID) • Clinical – Most severe form of primary immunodeficiency – 1/80,000 births – Failure to thrive, chronic diarrhea – Recurrent infections, pneumocystis pneumonia
- 14. SCID • Newborn screening • Genetic mutations affect both T and B cells in adaptive immune system – X-linked (most common) – Autosomal recessive – De novo mutations – Adenosine deaminase deficiency – Omenn syndrome (RAG genes)
- 15. Newborn Screening for SCID http://idfscidnewbornscreening.org/wp-content/uploads/2011/07/SCID-NBS-map.jpg Accessed on 4/22/13 - Images
- 18. SCIDS Defect http://www.immunopaedia.org.za/index.php?id=733 Accessed on 4/19/13 - Images
- 19. SCID • Treatment – BONE MARROW TRANSPLANT – Gene therapy – Enzyme replacement therapy – In utero stem cell replacement
- 20. SCID http://www.pharmaprojects.com/therapy_analysis/genether_0409.htm Accessed on 4/19/13 - Images
- 21. Hemophagocytic Lymphohistiocytosis (HLH) • Clinical – Fever – Hepatosplenomegaly – Lymphadenopathy – Jaundice – Rash
- 22. Hemophagocytic Lymphohistiocytosis (HLH) • Laboratory – 1.2 cases/million (rare) – All age groups: younger more likely genetic (primary) – Pancytopenia – Elevated ferritin levels – Elevated sIL-2r – Histopathology: activated macrophages ingest RBC’s, WBC’s and platelets
- 23. Distribution of Primary Immunodeficiency Diseases http://www.biomedsearch.com/attachments/00/21/17/05/21170549/431_2010_1358_Fig1_HTML.jpg Accessed on 1/22/13 - Images 23
- 24. Hemophagocytic Lymphohistiocytosis (HLH) http://en.wikipedia.org/wiki/File:Hemophagocytic_syndrome_-_cropped_-_very_high_mag.jpg Accessed on 4/22/13 - Images
- 25. HLH • Primary HLH – Five gene mutations – FHL1-5 • Secondary HLH – Infections – Lymphoma – Metabolic disease
- 26. Outcome for HLH • Without treatment, patients with familial HLH survived two months • In 1994, reported survival was 55% with median follow-up at 3.1 years • Before 2000, survival after bone marrow transplantation was 50 to 65% • Outcome may now be better with improved treatment regimens
- 27. X-linked Lymphoploliferative Syndrome • Long arm X chromosome • SH2D1A gene, XIAP gene (X-linked recessive) • 1 male per million • Epstein-Barr Virus (EBV) triggers hemophagocytic lymphohistiocytosis • Lymphoma • Treatment: stem cell transplant
- 28. HIV/AIDS • Human immunodeficiency virus • Acquired immunodeficiency syndrome
- 29. HIV History • Africa early 20th century • Primates infected with SIV (simian immunodeficiency virus) • Bushmeat infected humans with SIV and virus mutates into HIV • Urbanization and increased STD promotes spread in Africa • Virus introduced into the US in 1969?
- 30. HIV History • Increasing reports of a previously unknown disease reported after 1969 in US • In 1981, disease confirmed in US • In 1982, the disease is named AIDS (acquired immunodeficiency syndrome) • In 1983, report published in SCIENCE identifying HIV as a retrovirus
- 31. Epidemiology • 30 million deaths by 2009 • 34 million living with HIV/AIDS worldwide • In US in 2008, 1.2 million living with HIV infection • Sixth leading cause of death in ages 25 – 44 in US
- 32. HIV virus https://en.wikipedia.org/wiki/File:HIV_Virion-en.png Accessed on 4/22/13 - Images
- 33. HIV • Single stranded RNA virus • Viral encoded reverse transcriptase makes double stranded DNA • Viral integrase allows viral DNA to be spliced into human DNA • May remain dormant or code for new viruses to be made • HIV-1, HIV-2
- 34. Transmission • Blood transfusion • Sexual contact • Vertical transmission – mother to baby • IV drug abuse • Body fluid exposure only if contaminated with blood • Breast milk • Organ transplantation • Needle stick
- 35. Pathophysiology • Enters the body and get viral replication • Virus attaches to T lymphocytes, macrophages • CD4+ cells (helper) depleted at expense of CD8+ (suppressor) cell activation • Eventually majority of CD4+ cells are lost and immune system partially disabled leading to oppurtunistic infections and cancer
- 36. Clinical – Three Stages • Acute Infection • Latency Period • Acquired Immunodeficiency Syndrome
- 37. Acute Clinical Presentation https://en.wikipedia.org/wiki/File:Symptoms_of_acute_HIV_infection.svg Accessed on 4/22/13 - Images
- 39. Kaposi’s sarcoma http://www.nlm.nih.gov/medlineplus/ency/imagepages/2516.htm Accessed on 4/22/13 - Images
- 40. Clinical • Acquired Immunodeficiency Syndrome – Defined as CD4+ counts<200 or intercurrent diseases associated with HIV infection (pneumocystis pneumonia, Kaposi’s sarcoma) – Occurs in 50% of HIV + individuals within 10 years of infection if not treated
- 41. Treatment • HAART- highly active antiretroviral therapy – DNA analogs: reverse transcriptase inhibitors – Non DNA analogs: bind to enzyme (reverse transcriptase) and cause conformational change so cannot make DNA
- 42. Treatment http://www.nature.com/nature/journal/v410/n6831/fig_tab/410995a0_F3.html Accessed on 4/22/13 - Images
- 43. Conclusion • Outcomes for children with immunodeficiency dependent depends on the following: – Timely recognition – Adequate therapy and surveillance – The nature of the underlying disease
- 44. Thank you for attending • Immunodeficiency Syndromes, Part Three – T cell Deficiencies – Combined B- and T-cell Immunodeficiency – Acquired Immunodeficiency Disease Diseases of Immune Dysregulation
- 45. Questions?