Implications for Immunotherapy of Acute Radiation Syndromes. Part 2.
Immunodeficiency syndromes part 2
-
Upload
pediatric-home-service -
Category
Health & Medicine
-
view
1.499 -
download
2
description
Transcript of Immunodeficiency syndromes part 2
![Page 1: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/1.jpg)
Immunodeficiency SyndromesPart Two
Deficiencies of innate immune system and other well-defined immunodeficiency
syndromesJanuary 23, 2013
Roy C. Maynard, M.D.
![Page 2: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/2.jpg)
Review
Immunodeficiency Syndromes
Part OnePrimer on Immunology
May 23, 2012
2
![Page 3: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/3.jpg)
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
![Page 4: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/4.jpg)
Immunodeficiency Syndromes
Part TwoDeficiencies of innate immune system and other
well-defined immunodeficiency syndromes
4
![Page 5: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/5.jpg)
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
![Page 6: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/6.jpg)
http://www.hhmi.org/biointeractive/disease/immunology_primer/01.htmlAccessed on 1/18/13
Cells of the Immune System
6
![Page 7: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/7.jpg)
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
![Page 8: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/8.jpg)
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
![Page 9: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/9.jpg)
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
![Page 10: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/10.jpg)
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
![Page 11: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/11.jpg)
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
![Page 12: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/12.jpg)
Chronic Granulamatous Disease
http://www.health-pic.com/EX/09-19-02/1331341-1331368-962445-1674756.jpgAccessed on 1/22/13 - Images
12
![Page 13: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/13.jpg)
Brain Abscesses
http://www.stritch.luc.edu/lumen/MedEd/Radio/curriculum/Harrisons/Neuro/infection1a.jpgAccessed on 1/22/13 - Images
13
![Page 14: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/14.jpg)
Phagocytic Cell Defects
http://www.jgid.org/articles/2011/3/4/images/JGlobalInfectDis_2011_3_4_348_91056_f1.jpgAccessed on 1/22/13 - Images
14
![Page 15: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/15.jpg)
CGD – Chest Abscess
http://www.anatomybox.com/wp-content/uploads/2012/09/cgd-abscess.jpgAccessed on 1/22/13 - Images
15
![Page 16: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/16.jpg)
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
![Page 17: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/17.jpg)
Chediak-Higashi Syndrome
http://medlibes.com/uploads/Screen%20shot%202010-08-06%20at%206.16.41%20PM.pngAccessed on 1/22/13 - Images
17
![Page 18: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/18.jpg)
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
![Page 19: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/19.jpg)
Complement System
http://www.emc.maricopa.edu/faculty/farabee/biobk/biobookimmun.htmlAccessed on 1/22/13 - Images
19
![Page 20: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/20.jpg)
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
![Page 21: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/21.jpg)
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
![Page 22: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/22.jpg)
Distribution of Primary Immunodeficiency Diseases
http://www.biomedsearch.com/attachments/00/21/17/05/21170549/431_2010_1358_Fig1_HTML.jpgAccessed on 1/22/13 - Images
22
![Page 23: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/23.jpg)
Immunodeficiency
http://en.wikipedia.org/wiki/Primary_immunodeficiencyAccessed on 1/22/13
23
![Page 24: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/24.jpg)
24 of 37
Cells of the Immune System
http://www.hhmi.org/biointeractive/disease/immunology_primer/01.htmlAccessed on 1/18/13
24
![Page 25: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/25.jpg)
Immunoglobulins
• IgM- primary response• IgG- secondary and sustained
response• IgA- secretory• IgE- allergies, parasites• IgD- immunomodulation
25
![Page 26: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/26.jpg)
26 of 37
http://upload.wikimedia.org/wikipedia/commons/thumb/3/31/Mono-und-Polymere.svg/170px-Mono-und-Polymere.svg.pngAccessed on 1/22/13
Anatomy of an Immunoglobulin
26
![Page 27: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/27.jpg)
27 of 37
Immunoglobulin Switching
27
![Page 28: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/28.jpg)
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
![Page 29: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/29.jpg)
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
![Page 30: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/30.jpg)
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
![Page 31: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/31.jpg)
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
![Page 32: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/32.jpg)
Bruton’s Agammaglobulemia
http://trialx.com/curetalk/wp-content/blogs.dir/7/files/2011/05/diseases/Bruton'S_Agammaglobulinemia-2.jpgAccessed on 1/22/13 - Images
32
![Page 33: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/33.jpg)
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
![Page 34: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/34.jpg)
http://trialx.com/curebyte/2011/08/28/common-variable-immunodeficiency-photosAccessed on 1/22/13 - Images
Common Variable Immunodeficiency (CVID)
34
![Page 35: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/35.jpg)
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 transplant35
![Page 36: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/36.jpg)
Wiskott-Aldrich Syndrome
http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1114511-2412.jpgAccessed on 1/22/13 - Images
36
![Page 37: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/37.jpg)
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
![Page 38: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/38.jpg)
Ataxia Telangiectasia
http://drugline.org/img/ail/2456_2473_1.gifAccessed on 1/22/13 - Images
38
![Page 39: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/39.jpg)
IRAK-4 Deficiency
• Rare defect in innate immunity• Defect in pathogen recognition
receptor signaling• Recurrent pyogenic and ENT/airway
infections
39
![Page 40: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/40.jpg)
IRAK-4 Deficiency
http://www.rikenresearch.riken.jp/images/figures/hi_2437.jpgAccessed on 1/22/13 - Images
40
![Page 41: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/41.jpg)
IRAK 4 DeficiencyLung Abscess
http://www.stanford.edu/dept/radiology/radiologysite/images/Med%20students%201,%20chest/Pleura,%20empyema%20(1).pngAccessed on 1/22/13 - Images
41
![Page 42: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/42.jpg)
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 disorders42
![Page 43: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/43.jpg)
Conclusion
• Treatment options incude:– Prophylactic antibiotics– SQ gammaglobulin– IV gammaglobulin– Stem cell or bone marrow
transplantation– New biologicals– Gene therapy
43
![Page 44: Immunodeficiency syndromes part 2](https://reader033.fdocuments.net/reader033/viewer/2022061218/54b7f3f94a7959d5118b459f/html5/thumbnails/44.jpg)
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