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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
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
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
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
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
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
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
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