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Authors
Clinical Immunology: Primary
Immunodeficiency for General
Medical Audiences
Mark A. Posner, MD, FAAAAI
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Elena Perez, MD PhD FAAAAI
Jordan Orange, MD PhD FAAAAI
Javier Chinen, MD PhD FAAAAI
Charlotte Cunningham Rundles, MD PhD FAAAAI
Francisco A. Bonilla, MD PhD FAAAAI
Rebecca Buckley, MD FAAAAI
Richard Wasserman, MD PhD FAAAAI
Ricardo Sorensen, MD
Ramsay Fuleihan, MD
Debra Sedlak, MSN CPNP
With valuable contributions from members of the Primary
Immunodeficiency Diseases Committee
*Authors disclosed no relevant financial relationships
© AAAAI 2012
Content Experts
• Vivian Hernandez-Trujillo, M.D. FAAAAI
• John Sleasman, M.D.
• Maite de la Morena, M.D.
Main Objective: To provide fundamental
concepts on Primary Immunodeficiencies for
general medical audiences
*Content Experts disclosed no relevant financial relationships
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OUTLINE
The Immune System
a. Function
b. Components
II. Primary Immunodeficiency
a. Definition
b. Symptoms and Signs
c. Presentation – pattern of infections
III. Specific immunodeficiency diseases with cases
a. Antibody defects
b. Cellular defects
c. Phagocytic defects
d. Complement defects
The Immune System
I.
The Immune System
1.
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2.
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
Innate
Present from birth
Specificity is “pre-programmed”
Includes “non-immunological” cells (e.g. skin and cilia)
Adaptive
Develops during life with exposure to infection (memory)
Increases affinity with experience (specificity)
Two compartments:
 Cellular- Mediated by cells
 Humoral-Mediated by soluble factors
Memory and Specificity are key features
• What does it do?
• Recognizes pathogens (non-self)
• Organizes a defense response
• Facilitates pathogen destruction and elimination
Immune System Components
Cellular
Innate
Adaptive
Monocytes,
macrophages,
NK cells
T cells
Humoral
Complement
Antibody (B cells)
2
Monocyte/macrophages
Lymphoid organs/tissues
• Primary or central lymphoid organs
– Bone marrow – B cells
– Thymus – T cells
• Secondary or peripheral lymphoid organs
– Spleen
– Lymph nodes
– Organ-associated lymphoid tissue (gut, mucosaassociated lymphoid tissue [MALT], Peyer’s
patches), also skin
•
•
•
•
•
NK (natural killer) cells
• Lymphoid components of innate immunity
• Can kill cells alone or with antibodies
• Anti-tumor immunity
B cells
• Develop in the Bone marrow
• Mediate humoral specific immunity by producing
antibodies
Immunoglobulins/Antibodies
• NEUTRALIZE viruses, toxins by binding,
forms IMMUNE COMPLEXES
• OPSONIZE microbes for phagocytosis,
usually with complement
• Targets cells for cytotoxicity (antibodydependent cellular cytotoxicity, ADCC)
Monocytes, macrophages, dendritic cells
Interact with microbes and secrete cytokines
Ingest, process and present antigens to T cells
Are activated by T cells to kill microbes
Use complement and antibody to phagocytose
microbes
T cells
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•
•
•
Develop in the Thymus
Mediate specific cellular immunity, kill infected cells
Provide help to B cells for antibody production
Regulate immune responses through cytokine
secretion
3
Complement
OUTLINE
The Immune System
a. Function
b. Components
II. Primary Immunodeficiency
a. Definition
b. Symptoms and Signs
c. Presentation – pattern of infections
III. Specific immunodeficiency diseases with cases
a. Antibody defects
b. Cellular defects
c. Phagocytic defects
d. Complement defects
I.
• System of soluble proteins and cellular receptors
• Functions alone or with antibodies to:
– Kill microbes, lyse cells
– Opsonize microbes for phagocytosis
• Chemotaxis of monocytes and neutrophils
• Contributes to inflammation after tissue damage
Primary Immunodeficiencies
Primary Immunodeficiency Diseases
combined cellular
and antibody
deficiencies 15%
Definition:
cellular
deficiencies 5%
Primary immunodeficiency diseases are
conditions characterized by intrinsic
deficits within the immune system and
are caused by inherited or de novo
genetic defects
phagocytic
deficiencies 10%
complement
deficiencies 5%
antibody
deficiencies 65%
Modified from Stiehm: Immunologic Disorders of Infants and
Children – Fifth Edition, Chapter 12, pg 293
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Symptoms of immunodeficiency
1. Infections
-
Frequent, severe, unusual organisms, difficult
to treat
Failure to thrive
10 Warning
Signs of
Immunodeficiency*
2. Autoimmune disease
-
Immune system no longer able to properly
distinguish self from non-self
3. Immune dysregulation
-
Impaired tumor surveillance
Hematopoietic malignancy
*The Jeffrey Modell
Foundation Medical
Advisory Board
Diagnosis of Primary Immunodeficiency
• Medical history
• Family history
• Characteristic infectious susceptibilities
and patterns of infection
• Physical examination
• Laboratory testing
• Referral to an immunologist
• Specific diagnosis and treatment
• Co-management with primary care
www.primaryimmune.org
5
Immune effector mechanisms
Antibody
production
T cell help
B
B cell / humoral / antibody deficiencies
Antibody
production
T cell help
B
T
T
M
M
+ Complement
+ Complement
Intracellular
killing
PMN
PMN
Extracellular
killing
Intracellular
killing
Cytotoxicity
Cytotoxicity
Antibody deficiency: pattern of infections
• Bacteria: pneumococcus, H. flu, Moraxella, Staph
aureus, meningococcus, Pseudomonas,
Campylobacter
Mycoplasma, Ureaplasma
• Viruses: common respiratory and esp. enteroviruses
(including vaccine strains), rotavirus
Cellular immunodeficiency: Defects in the
IL12/IFNγ axis
Antibody
production
T cell help
B
T
M
+ Complement
• Protozoa: Giardia, Cryptosporidium
Intracellular
killing
PMN
Cytotoxicity
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Cellular immunodeficiency: pattern of infections
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Mycobacteria, esp. atypical and including BCG
Salmonella
Candida
Herpes viruses
Pneumocystis
Combined immunodeficiency
Antibody
production
T cell help
B
T
M
+ Complement
Intracellular
killing
PMN
Cytotoxicity
Combined immunodeficiency: pattern of
infections
Phagocyte defects
Antibody
production
T cell help
B
T
M
+ Complement
Intracellular
killing
Same as for antibody and cellular deficiencies plus:
• Bacteria: Listeria, enteric flora
• Viruses: herpesviruses, RSV, influenza, parainfluenza,
measles (also vaccine strains)
• Fungi: Pneumocystis, Candida, Cryptococcus,
Histoplasma
• Protozoa: Toxoplasma, Cryptosporidium
PMN
Cytotoxicity
7
Complement deficiency
Phagocyte defects: pattern of infections
Antibody
production
• Bacteria: catalase-positive
T cell help
B
– Most commonly: Staphylococcus aureus, Burkholderia
(Pseudomonas) cepacia, Serratia marcescens, Nocardia,
– Also: Klebsiella, enteric flora
T
M
• Mycobacteria including BCG
• Fungi: Candida, Aspergillus, Paecilomyces
+ Complement
Intracellular
killing
PMN
Cytotoxicity
Complement deficiency: pattern of infections
• Encapsulated organisms:
– Neisseria (terminal MAC components)
– Pyogenic infection
• Autoimmune disease frequent
– (early components)
OUTLINE
The Immune System
1. Function
2. Components
I. Primary Immunodeficiency
1. Definition
2. Symptoms and Signs
3. Presentation – pattern of infections
II. Specific immunodeficiency diseases with cases
•
1.
2.
3.
4.
Antibody defects
Cellular defects
Phagocytic defects
Complement defects
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Flow Cytometry: T cells vs B cells
Case #1: Antibody deficiencies
Diagnosis: X-linked Agammaglobulinemia
Infection Susceptibility: pyogenic infections, viral meningoencephalitis, vaccine strain poliomyelitis, mycoplasma
arthritis
Control
Patient
10%
0%
CD19
Laboratory
• IgG < 100 mg/dL
(650-1,500)
• IgA 0-10
(70-400)
• IgM 0-20
(50-300)
• No specific antibody
• Cellular immunity
normal
CD19
History
• 2 yr old boy
• Frequent ear infections
• 3 episodes of pneumonia
• One bacterial meningitis
• One pneumococcal
sepsis
CD3
CD3
Common Variable Immunodeficiency
Infection Susceptibility: Bacteria, common respiratory and
enteroviruses (including vaccine strains), rotavirus, giardia,
cryptosporidium
Inheritance: X-linked
Clinical Features: Recurrent sinopulmonary infections,
bronchiectasis, diarrhea, arthritis, giardiasis, autoimmunity
(20%), asthma (10%), lymphoproliferative disease, gastric
CA and lymphoma
Diagnosis:
Inheritance: sporadic, autosomal recessive
Clinical Features: infancy/childhood with recurrent
sinopulmonary pyogenic infections, 25% with neutropenia
Absent B cells
Approximately 50% positive family history
IgG usually <100 mg/dL
B cells < 2% of lymphocytes (~ 0.05-0.3%)
Normal T cell number and function
Diagnosis: Hypogammaglobulinemia (IgG, IgA, IgM), B
cells present. Impaired antibody response
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Antibody Deficiencies: Specific Diagnoses
Agammaglobulinemia
• X-linked
Case #2: Cellular and Combined
Immune Deficiencies
• Autosomal Recessive
Hyper IgM Syndrome (HIGM)
• X-linked (lack of T cell help)
• Autosomal Recessive
Common Variable Immunodeficiency (CVID)
IgG Subclass Deficiency
Specific Antibody Deficiency
Transient Hypogammaglobulinemia of Infancy
TREATMENT: Immunoglobulins, antibiotic prophylaxis
Case #2: Combined immunity deficiencies
History
• Born term
• Uneventful neonatal
course
• At 4 weeks, progressive
generalized dermatitis.
• Intermittent colic,
emesis, and diarrhea.
• Failure to thrive.
• Skin findings as above
• Diffuse
lymphadenopathy
Laboratory
IgG 155 mg/dL
IgA <7 mg/dL
IgM <5 mg/dL
Low IgE
Lymphocytes 9,000/mm3
Eos 3,500/mm3
CD3CD4 61%
CD3CD8 20%
CD19 1%
PHA 10% of control
T cells of host origin & oligoclonal
Sever Combined Immunodeficiency
(SCID)
Infection Susceptibility: All infectious organisms including
live vaccine strains and opportunistic infections.
Clinical Features: Failure to thrive, chronic diarrhea,
erythroderma or other skin eruption. Specific gene defects
may have associated features.
Inheritance: X-linked (most common) or autosomal
recessive
Diagnosis: Lymphopenia in most, diminished or absent T
cells in most (maternal T cell engraftment or aberrant
oligoclonal T cells in Omenn, may confuse the picture),
poor/absent in vitro mitogen-induced T cell proliferation in
all.
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Treatment of Severe Combined Immunodeficiency
• Curative:
– Stem cell transplantation
– Gene therapy (ADA, XL-SCID) Experimental
• Adjuvant
– Enzyme replacement (PEG-ADA)
– Prophylactic antibiotics
– IVIG
– Avoidance live viral vaccines
– Irradiation of blood products
– CMV negative blood products only
Cellular and Combined Immune Deficiencies:
Specific Diagnoses
SCID
Wiskott Aldrich
Ataxia Telangiectasia
DiGeorge Syndrome
Chronic Mucocutaneous Candidiasis
IL-12/IFN gamma axis
X-linked lymphoproliferative disorder
Ectodermal dysplasia with immune deficiency
WHIM syndrome
Case #3: Disorders of Phagocytes
Case #3: DHR test for neutrophil oxidative burst
Control
Patient
History
• 15mo male with
respiratory distress
Prestimulation
• Chest x-ray with “white
out” on right side
• Unresponsive to
antibiotics
• CT scan with abscess
Poststimulation
• Broncheoaveolar lavage:
Hyphae
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Diagnosis: Chronic Granulomatous Disease
Infection Susceptibility: catalase positive organisms, and
indolent fungal infections.
Clinical Features: Recurrent infections. Granulomas of skin,
liver, lungs, lymph nodes, viscera, bones, joints. GI/GU
obstruction secondary to granulomas
Diagnosis: Neutrophil oxidative burst assay by flow cytometry
using dihydrorhodamine 123 (replacing NBT test)
Treatment:
• Prophylactic antibiotics
• Gamma interferon
• Bone marrow transplantation
Pathway
s
Case #4: Complement deficiency
Classical
Immune
Complexes
C1q, C1e,
C1s, C4,
C2
Chemotaxis
Lectin
Alternative
Pathogen
Oligosaccharides
Pathogen
surfaces
MBL,
MASP1/2
, C4, C2
FB, FD,
C3
C3
Opsonization B
cell activation
C5
C6
C7
C8
C9
Lysis
Phagocyte defects: Specific Diagnoses
• Chronic granulomatous disease
– X-linked
– Autosomal recessive
• Chediak-Higashi syndrome
• Leukocyte adhesion deficiency
• Neutrophil specific granule deficiency
• Congenital agranulocytosis
Complement Component Deficiency
:History
• 15 yo male with fever
• altered mental status
• petechial rash
Infection Susceptibility and Clinical Features: Recurrent
pyogenic infection and also connective tissue disease
(especially C2 and C4)
Laboratory:
• Culture and gram stain
of CSF = N. meningitidis
• CH50 = zero
• Terminal complement
components analysis:
Deficiency of C6.
• Deficiency of regulatory protein C1 esterase inhibitor is
associated with angioedema
Late component deficiency (C5 – 9) recurrent Neisseria
species infection
Diagnosis: CH50 for classical pathway, AH50 for alternative
pathway, and/or individual complement component levels
Treatment:
• Prophylactic antibiotics
• Immunizations with bacterial polysaccharide vaccines
(e.g. Pneumococcal vaccines)
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Complement Disorders : Specific Diagnoses
Diagnostic Tools for Antibody Deficiency
Classical component deficiency: Early (C1-C4); Late (C5-C9)
Alternative component deficiency: Properidin, Factor D
Regulatory Components: C1 inhibitor – HAE, factor I, factor H
Lectin pathway deficiency: Mannose Binding Lectin
C2 deficiency most commonly reported
SLE-like autoComponent(s) immune disease
C1, C2, C4
Yes
C3
No
C5, C6, C7
Yes
C8, C9
No
Properdin
Yes
Factor D
No
Bacterial infections
Multiple
Multiple, severe
Neisseria
Neisseria
Multiple
Multiple
Diagnostic Tools for T cell deficiency
Diagnostic tools for Complement Deficiency
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Diagnostic tools for Neutrophil defects
Summary
• In less than 40 years, we progressed remarkably from the
description of newly discovered Primary Immunodeficiency
Diseases to the development of cellular and molecular cures.
• Molecular immunology is uncovering precise defects in many
immunodeficiencies
• Prompt diagnosis and appropriate therapy are life saving
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