Immunodeficiency Syndromes Part Three
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The document discusses various primary immunodeficiency syndromes including T cell deficiencies like DiGeorge syndrome and X-linked hyper IgM syndrome. It also covers combined B- and T-cell immunodeficiencies such as severe combined immunodeficiency disease (SCID) as well as acquired immunodeficiency diseases and diseases of immune dysregulation including hemophagocytic lymphohistiocytosis (HLH), X-linked lymphoproliferative syndrome, and HIV/AIDS. Treatment options discussed include bone marrow transplantation, gene therapy, and highly active antiretroviral therapy. Outcomes for children with immunodeficiencies depend on timely diagnosis, adequate treatment and surveillance, and the underlying disease.
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Immunodeficiency Syndromes Part Three
- 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?