Immunodeficiency syndromes part 2

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Pediatric Home Service Medical Director, Dr. Roy Maynard discusses deficiencies of innate immune system and other well-defined immunodeficiency syndromes.

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Immunodeficiency syndromes part 2

  1. 1. Immunodeficiency Syndromes Part Two Deficiencies of innate immune system and other well- defined immunodeficiency syndromes January 23, 2013 Roy C. Maynard, M.D.
  2. 2. Review Immunodeficiency Syndromes Part One Primer on Immunology May 23, 2012 2
  3. 3. Conclusions – Part One • The immune system developed for your protection • Involves complex interactions between antigens, immune cells, and cytokines • Responsible for killing bacteria, viruses, fungi, and parasites • Deficits within the immune system may be congenital or acquired and lead to immunodeficiency • Relative to transplantation and tumor immunology • Imbalances in the regulatory mechanisms of the immune system may lead to organ-specific or nonorgan-specific autoimmune diseases 3
  4. 4. Immunodeficiency Syndromes Part Two Deficiencies of innate immune system and other well- defined immunodeficiency syndromes 4
  5. 5. Objectives • Identify the most common immunodeficiency disorders • Recognize the clinical presentation for patients with immunodeficiency disorders • Understand treatment options for patients with immunodeficiency disorders 5
  6. 6. http://www.hhmi.org/biointeractive/disease/immunology_primer/01.html Accessed on 1/18/13 Cells of the Immune System 6
  7. 7. Clinical Presentation • Medical History – Recurrent bacterial infections – 2 or more severe infections (pneumonia, sepsis, meningitis, osteomyelitis) – Atypical presentation – Unusually severe course, impaired response to treatment – Opportunistic pathogen – Recurrent infection same pathogen 7
  8. 8. Clinical Presentation • Medical History – Recurrent abscesses in internal organs or skin – Failure to thrive with chronic diarrhea – Prolonged candidiasis (oral/skin) – Delayed umbilical cord separation >4 weeks – Delayed shedding primary teeth – Family history – Unexplained bronchiectasis – Autoimmune disease 8
  9. 9. Clinical Presentation • Physical Exam – Dysmorphic features, face, microcephaly – Albinism, abnormal hair, eczema, dermatitis – Telangiectasia, ataxia – Gingivitis, oral ulcers – Abnormal wound healing – Absence of lymph tissue (nodes, tonsils) or no thymus on CXR – Lymphadenopathy, organomegaly, digital clubbing 9
  10. 10. Phagocytic Cell Defects • Presentation – Recurrent non-superficial pyogenic infections and recurrent ENT and airway infections – Opportunistic fungal infections – Aspergillus, Staphylococcus, Serratia, Nocardia • Killing Defect – Chronic Granulomatous Disease (CGD) • Chemotaxis Defect – Hyper IgE syndrome (Also called Job Syndrome) – Leukocyte Adhesion Defect (LAD) – Schwachman-Diamond Syndrome (SDS) 10
  11. 11. Phagocytic Cell Defects Continued • Chronic Granulomatous Disease – Phagocytes(monocytes and neutrophils) fail to produce reactive oxygen intermediates (superoxides) and hydrogen peroxide that kill bacteria – 75% inherited X-linked recessive, remainder autosomal recessive (15% are girls) – 20 new cases a year; 1/200,000 births – Diagnosis by fluorescent chemical after exposure to hydrogen peroxide in phagocytes – Prophylactic and early treatment to prevent infections – Gamma interferon treatment may reduce infections by 70% 11
  12. 12. Chronic Granulamatous Disease http://www.health-pic.com/EX/09-19-02/1331341-1331368-962445-1674756.jpg Accessed on 1/22/13 - Images 12
  13. 13. Brain Abscesses http://www.stritch.luc.edu/lumen/MedEd/Radio/curriculum/Harrisons/Neuro/infection1a.jpg Accessed on 1/22/13 - Images 13
  14. 14. Phagocytic Cell Defects http://www.jgid.org/articles/2011/3/4/images/JGlobalInfectDis_2011_3_4_348_91056_f1.jpg Accessed on 1/22/13 - Images 14
  15. 15. CGD – Chest Abscess http://www.anatomybox.com/wp-content/uploads/2012/09/cgd-abscess.jpg Accessed on 1/22/13 - Images 15
  16. 16. Other Phagocytic Defects • Chediak-Higashi Syndrome (CHS) – Autosomal recessive – Impaired phagocytosis and killing bacteria – Albinism, peripheral neuropathy, lymphoma- like-syndrome – Diagnosis CHS1 gene, biopsy giant inclusions in bone marrow 16
  17. 17. Chediak-Higashi Syndrome http://medlibes.com/uploads/Screen%20shot%202010-08-06%20at%206.16.41%20PM.png Accessed on 1/22/13 - Images 17
  18. 18. Leukocyte Adhesion Deficiency • Rare 1/100,000 • Autosomal recessive • Cannot migrate (chemotaxis) out of the blood vessel • Diagnosis (high neutrophil levels) • Absent CR3 protein • Do not form abscesses • Treatment bone marrow transplant 18
  19. 19. Complement System http://www.emc.maricopa.edu/faculty/farabee/biobk/biobookimmun.html Accessed on 1/22/13 - Images 19
  20. 20. Complement System • Complex series of 20 proteins in plasma • Enzyme activation of cascade • Complement facilitates phagocytosis • Complement (C3b) binds to bacteria and allows recognition by phagocytes to engulf • May stimulate (C3a and C5a) phagocytes make reactive oxygen intermediates and enhance expression of cell surface receptors • Trigger degranulation of mast cells and granulocytes • Attract other inflammatory cells • Part of anaphylaxis 20
  21. 21. Complement System • Clinical Presentation – Recurrent meningitis – Recurrent sepsis – Recurrent pyogenic infections with encapsulated organisms (C3 deficiency) – Atypical hemolytic uremic syndrome – Systemic lupus erythematosus (C1, C2, C4 deficiency) 21
  22. 22. 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 22
  23. 23. Immunodeficiency http://en.wikipedia.org/wiki/Primary_immunodeficiency Accessed on 1/22/13 23
  24. 24. 24 of 37 Cells of the Immune System http://www.hhmi.org/biointeractive/disease/immunology_primer/01.html Accessed on 1/18/13 24
  25. 25. Immunoglobulins • IgM- primary response • IgG- secondary and sustained response • IgA- secretory • IgE- allergies, parasites • IgD- immunomodulation 25
  26. 26. 26 of 37 http://upload.wikimedia.org/wikipedia/commons/thumb/3/31/Mono-und-Polymere.svg/170px-Mono- und-Polymere.svg.png Accessed on 1/22/13 Anatomy of an Immunoglobulin 26
  27. 27. 27 of 37 Immunoglobulin Switching 27
  28. 28. IgG Subclasses • IgG1- most common IgG (60-70%), antibodies to proteins; diptheria, tetanus, viruses • IgG2-polysaccharide antigens; hemophilus, pneumococcus • IgG3-antibodies to proteins; diptheria, tetanus, viruses • IgG4 • Natural history- IgG subclass deficiency associated with recurrent ear, sinus and lung infections, usually resolves by adulthood • Treatment prophylactic antibiotics and gammaglobulin 28
  29. 29. Selective IgA Deficiency • Relatively common • 1/333 births • Generally asymptomatic • May be associated with recurrent respiratory and urinary tract infections • May be associated with other disorders (e.g., celiac disease) 29
  30. 30. Hyper IgM Syndrome • Genetic disorder (x linked, some AR) • B cells cannot switch from IgM production to IgG production • Normal or elevated IgM production, other Ig low • Low neutrophils and platlets • Increased risk for infections • Prophylactic antibiotics, IV IgG 30
  31. 31. Predominantly Antibody Deficiencies • X-linked (Bruton-type) agammaglobulinemia – X chromosome – Arrest in early B-cell maturation – Males – Pyogenic infections (staph, strep A, Neisseria, Haemophilus, pneumocystis – Treatment gammaglobulin infusions 31
  32. 32. Bruton’s Agammaglobulemia http://trialx.com/curetalk/wp-content/blogs.dir/7/files/2011/05/diseases/Bruton'S_Agammaglobulinemia-2.jpg Accessed on 1/22/13 - Images 32
  33. 33. Common Variable Immunodeficiency (CVID) • Defined by decrease of 2 out of 3 immunoglobulins (B cell defect) • Decreased response to immunization in children > 2 years • Recurrent ENT and airway infections • 1:50,000 • Genetic basis • Treatment: gammaglobulin 33
  34. 34. http://trialx.com/curebyte/2011/08/28/common-variable-immunodeficiency-photos Accessed on 1/22/13 - Images Common Variable Immunodeficiency (CVID) 34
  35. 35. Wiskott-Aldrich Syndrome • Eczema, thrombocytopenia, combined immunodeficiency (T and B cells) • Low IgM • X-linked, 4/million, WASp gene • Increased risk for infection, autoimmune disease, malignancy • Treatment gammaglobulin, spleenectomy, bone marrow transplant 35
  36. 36. Wiskott-Aldrich Syndrome http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1114511-2412.jpg Accessed on 1/22/13 - Images 36
  37. 37. Ataxia Telangiectasia • Ataxia and scleral telangiectasia • Low immunoglobulins and abnormal T cell responses • Autosomal recessive • Impaired DNA repair mechanisms (cerebellar degeneration) • Inceased risk for cancer • Recurrent sinopulmonary disease • Treat gammaglobulin 37
  38. 38. Ataxia Telangiectasia http://drugline.org/img/ail/2456_2473_1.gif Accessed on 1/22/13 - Images 38
  39. 39. IRAK-4 Deficiency • Rare defect in innate immunity • Defect in pathogen recognition receptor signaling • Recurrent pyogenic and ENT/airway infections 39
  40. 40. IRAK-4 Deficiency http://www.rikenresearch.riken.jp/images/figures/hi_2437.jpg Accessed on 1/22/13 - Images 40
  41. 41. IRAK 4 Deficiency Lung Abscess http://www.stanford.edu/dept/radiology/radiologysite/images/Med%20students%201,%20chest/Pleura,%20empyema%20(1).png Accessed on 1/22/13 - Images 41
  42. 42. Conclusion • 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 42
  43. 43. Conclusion • Treatment options incude: – Prophylactic antibiotics – SQ gammaglobulin – IV gammaglobulin – Stem cell or bone marrow transplantation – New biologicals – Gene therapy 43
  44. 44. Thanks for Attending • Next presentation will include: – Diseases of immune dysregulation – Severe combined immunodeficiency – Predominantly T-cell disorders – Autoinflammatory disorders • Watch for notification – the next lecture will occur in April. 44

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