Immunodeficiency SyndromesPart Two

Deficiencies of innate immune system and other well-defined immunodeficiency

syndromesJanuary 23, 2013

Roy C. Maynard, M.D.

Review

Immunodeficiency Syndromes

Part OnePrimer on Immunology

May 23, 2012

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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

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Immunodeficiency Syndromes

Part TwoDeficiencies of innate immune system and other

well-defined immunodeficiency syndromes

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Objectives

• Identify the most common immunodeficiency disorders

• Recognize the clinical presentation for patients with immunodeficiency disorders

• Understand treatment options for patients with immunodeficiency disorders

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http://www.hhmi.org/biointeractive/disease/immunology_primer/01.htmlAccessed on 1/18/13

Cells of the Immune System

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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

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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

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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

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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)

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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%

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Chronic Granulamatous Disease

http://www.health-pic.com/EX/09-19-02/1331341-1331368-962445-1674756.jpgAccessed on 1/22/13 - Images

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Brain Abscesses

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

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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

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CGD – Chest Abscess

http://www.anatomybox.com/wp-content/uploads/2012/09/cgd-abscess.jpgAccessed on 1/22/13 - Images

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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

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Chediak-Higashi Syndrome

http://medlibes.com/uploads/Screen%20shot%202010-08-06%20at%206.16.41%20PM.pngAccessed on 1/22/13 - Images

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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

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Complement System

http://www.emc.maricopa.edu/faculty/farabee/biobk/biobookimmun.htmlAccessed on 1/22/13 - Images

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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

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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)

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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

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Immunodeficiency

http://en.wikipedia.org/wiki/Primary_immunodeficiencyAccessed on 1/22/13

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Cells of the Immune System

http://www.hhmi.org/biointeractive/disease/immunology_primer/01.htmlAccessed on 1/18/13

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Immunoglobulins

• IgM- primary response• IgG- secondary and sustained

response• IgA- secretory• IgE- allergies, parasites• IgD- immunomodulation

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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

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Immunoglobulin Switching

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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

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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)

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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

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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

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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

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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

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http://trialx.com/curebyte/2011/08/28/common-variable-immunodeficiency-photosAccessed on 1/22/13 - Images

Common Variable Immunodeficiency (CVID)

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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

Wiskott-Aldrich Syndrome

http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1114511-2412.jpgAccessed on 1/22/13 - Images

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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

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Ataxia Telangiectasia

http://drugline.org/img/ail/2456_2473_1.gifAccessed on 1/22/13 - Images

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IRAK-4 Deficiency

• Rare defect in innate immunity• Defect in pathogen recognition

receptor signaling• Recurrent pyogenic and ENT/airway

infections

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IRAK-4 Deficiency

http://www.rikenresearch.riken.jp/images/figures/hi_2437.jpgAccessed on 1/22/13 - Images

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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

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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

Conclusion

• Treatment options incude:– Prophylactic antibiotics– SQ gammaglobulin– IV gammaglobulin– Stem cell or bone marrow

transplantation– New biologicals– Gene therapy

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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.

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