This document summarizes immunodeficiency disorders, including deficiencies of the innate immune system and other well-defined syndromes. It discusses clinical presentations and treatments for disorders like chronic granulomatous disease, hyper IgE syndrome, complement deficiencies, selective IgA deficiency, common variable immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, and IRAK-4 deficiency. The conclusion emphasizes that immunodeficiency disorders have a variety of genetic causes and treatments including antibiotics, immunoglobulin therapies, stem cell transplantation, and gene therapy.

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. Review
Immunodeficiency Syndromes
Part One
Primer on Immunology
May 23, 2012
2

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. Immunodeficiency Syndromes
Part Two
Deficiencies of innate immune system and other well-
defined immunodeficiency syndromes
4

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. http://www.hhmi.org/biointeractive/disease/immunology_primer/01.html
Accessed on 1/18/13
Cells of the Immune System
6

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. 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. 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. 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. 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. 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. Brain Abscesses
http://www.stritch.luc.edu/lumen/MedEd/Radio/curriculum/Harrisons/Neuro/infection1a.jpg
Accessed on 1/22/13 - Images
13

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. CGD – Chest Abscess
http://www.anatomybox.com/wp-content/uploads/2012/09/cgd-abscess.jpg
Accessed on 1/22/13 - Images
15

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. 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. 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. Complement System
http://www.emc.maricopa.edu/faculty/farabee/biobk/biobookimmun.html
Accessed on 1/22/13 - Images
19

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. 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. 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. Immunodeficiency
http://en.wikipedia.org/wiki/Primary_immunodeficiency
Accessed on 1/22/13
23

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. Immunoglobulins
• IgM- primary response
• IgG- secondary and sustained response
• IgA- secretory
• IgE- allergies, parasites
• IgD- immunomodulation
25

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 of 37
Immunoglobulin Switching
27

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. 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. 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. 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. 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. 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. http://trialx.com/curebyte/2011/08/28/common-variable-immunodeficiency-photos
Accessed on 1/22/13 - Images
Common Variable
Immunodeficiency (CVID)
34

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. Wiskott-Aldrich Syndrome
http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1114511-2412.jpg
Accessed on 1/22/13 - Images
36

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. Ataxia Telangiectasia
http://drugline.org/img/ail/2456_2473_1.gif
Accessed on 1/22/13 - Images
38

39. IRAK-4 Deficiency
• Rare defect in innate immunity
• Defect in pathogen recognition receptor
signaling
• Recurrent pyogenic and ENT/airway
infections
39

40. IRAK-4 Deficiency
http://www.rikenresearch.riken.jp/images/figures/hi_2437.jpg
Accessed on 1/22/13 - Images
40

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. 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. Conclusion
• Treatment options incude:
– Prophylactic antibiotics
– SQ gammaglobulin
– IV gammaglobulin
– Stem cell or bone marrow transplantation
– New biologicals
– Gene therapy
43

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