Transcript IMMUNOLOGIC DEFICIENCY SYNDROMES

DISEASES OF IMMUNITY
Raymond L. Konger, M.D.
Associate Professor
[email protected]
Robbins Pathologic
Basis of Disease, 8th Ed.
Chapter 6
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Systemic autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
FIGURE 6-1 The principal classes of lymphocytes and their functions in
adaptive immunity.
CD4+ Th Development
Naive
ThP
Ag:MHC II
APC
Uncommitted
Th0
IL-2
IL-12/ IFN-g
IL-4
Th1
IFN-g
IL-2, TNF-a
Th2
IL-4, IL-5
TGF-b
TGF-b
IL-23
IL-6
FoxP3 (-/-)
= AI disease
CD4+/CD25+
Th17
Treg
IL-17, IL-22,
PMN / Monocyte
Chemokines
TGF-b
IL-10
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Systemic autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
Central T-cell Tolerance
Central tolerance: Clonal deletion of self-reactive
T cells in thymus.
 First: Positive selection for T-cells recognizing MHC
molecules (cells lacking recognition are deleted).
 Second: Negative selection for cells with high affinity
interaction with self antigens (cells deleted).
 Some T-cells that recognize self Ag are converted to Treg cells.
AIRE (Autoimmune regulator): Transcriptional regulator
induces “peripheral Ag” expression in thymic cells
(Mutated in autoimmune polyendocrinopathy)
Initiation of Adaptive Immune Response by Professional APCs:
Dendritic Cells
Activated APC:
High CD80/86 ( )
+ Ag presentation MHCI
&II ( )
Pathogen
Immature APC:
CD80/86 (B7.1/7.2) Low
Activated APC:
Migrates to LN for Presentation
of Ag to CD4 & CD8 cells
Migration and homing
(e.g to High Endothelial Venules)
Requires Specific Chemokines (e.g.
CCL19/21) & Adhesion
Receptors (e.g. ICAM-1)
Ag:MHCI & II
processing
CD80/86
CD80/86 interaction
with CD28 (T-Cells)
Is Critical
T-cell peripheral tolerance: CD80/86 (B7.1/7.2) costimulation
Activation vs. Tolerance
Dependent on maturation state of APC cells.
Immature APC cells: Low MHC Class I & II and CD80/86
(B7.1/7.2) co-stimulatory molecules
Mature APC cells: Increased MHC & CD80/86
T-cells also express
inhibitory B7 receptor,
CTLA-4
((-/-) mice assoc. with
AI disease)
Polymorphisms assoc.
with human AI disease
FoxP3(-/-)
CD-28
CTLA-4
Treg
IL-10
TGF-b
APC maturation:
Viral syndromes often
precede AI onset
Immune privilege:
eyes, testes, fetal trophoblast
Other T-cell : APC co-receptors
Anti-PD-1 or anti-CTLA-4: Tumor Immunotherapy
B-cell Tolerance
Central (BM):
• Immature B-cells exposed to high levels of
circulating self antigens undergo receptor editing
(BCR rearrangements in hypervariable region
that do not recognize self).
• If not successful, undergo apoptosis
B-cell Activation: Peripheral Tolerance
1. B-cell Antigen Recognition and
BCR Clustering (Mature B-cell)
or TI-Antigens (e.g., LPS)
2. T-cell antigen Recognition
and CD40 Co-stimulation
(Naïve B-cell)
Ag
MHC-II / TCR
Ag
B-cell
C3b
CD21
B-cell
Ag
CD40 CD40L
CD4+
T-cell
EBV
B-cell
C3b
Ab production
MHC-II upregulation
IFN-g
IL-4, IL-2
B-cell class switch &
Proliferation & Affinity Maturation
T-cell independent antigens:
(e.g. Pokeweed mitogen &
Carbohydrate antigens)
Induce low affinity IgM
and no memory cells
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
Comparisons of Type I-IV Hypersensitivity Reactions
Type I: IgE mediated “allergic”
response
Primary Mediators (preformed granules)
Histamine (Antihistamines):
Chemotactic factors: (LTB4, Eosinophil chemotactic factor)
Secondary Mediators (Lipid mediators)
Cysteinal Leukotrienes (C4, D4), PGD2, PAF
CysLT1 receptor antagonists: zafirlukast (Accolate),
montelukast (Singulair).
5-LO inhibitors: Zileuton (Zyflow)
Secondary Mediators (Cytokines)
TNF
IL-4, IL-5
Early response: Wheel and flare / bronchospasm (LKT C4/D4,
PAF) and mucous hypersecretion: vasodilation (histamine,
PAF); vascular permeability (histamine, PAF, LKT C4/D4).
Late-phase response: Recruitment of eosinophils, basophils,
neutrophils, CD4+ (TH2). Tissue remodeling.
Extreme Early Response:
Anaphylaxis
Fatal acute laryngeal edema during an
anaphylactic reaction to penicillin.
Asthma: Tissue Remodeling
Mucus Plug
Basement membrane
thickening
Inflammation with
eosinophils
Also: CD4+/Th2 NK-T cells
Type 2 Hypersensitivity: AntibodyMediated Reactions
In all cases:
Immune reaction against
Ab/complement bound to cell or tissue
Type II: Cytotoxic Antibody Mediated
Complement
+ Ab
C5-9
C3b
Target
Cell
Fc
Receptor
Macrophage
Membrane
Attack
Complex
Osmotic
Lysis
C3b
Opsonized
Cell
C3b
Receptor
Phagocytosis
Ab binding to Ag on cell results in complement fixation and
opsonization, resulting in lysis or phagocytosis (e.g. transfusion
reaction, AI hemolytic anemia, AI thrombocytopenia)
Type II: Antibody Dependent Cellular Cytotoxicity
Ab binding to cells activates effector cells: NK cells & also
Monocytes, PMNs, Eosinophils, that lyse Ab-coated cells via
cytotoxic mechanisms (e.g. granzyme/perforin) (No phagocytosis).
Eos use this mechanism to destroy parasites.
Type II: Antireceptor antibodies
Antibody has natural
ligand activity
(Graves Disease)
Antibody has natural
ligand blocking
activity
(Myasthenia gravis)
Diseases associated with Type II
antibody-mediated reactions:
Goodpasture’s Syndrome -- Type IV collagen
Bullous pemphigoid -- skin basement membrane
Pernicious anemia -- intrinsic factor
Acute rheumatic fever -- antibodies against
streptococcus cross react with heart
Erythroblastosis fetalis -- Rh D antigen
Transfusion reactions -- ABO and minor antigens
Aschoff Bodies:
Hallmark of Rheumatic
Fever
Granulomatous lesions that
follow necrosis/degenerative
phase and precedes fibrosis
(Found in only a small
subset of patients)
Anitschkow
cell
Aschoff Giant
Cell
Lymphocyte
FB
Type III: Immune Complex
Phase 1: Formation of immune complexes in the circulation
Phase 2: Deposition of the immune complexes in various tissues
(vasculitis, glomerulonephrits, or arthritis)
Phase 3: An inflammatory reaction provoked by activation of
PMNs and macrophages by Fc or C3b receptors.
Immune Complex Vasculitis:
Fibrinoid necrosis & infiltrates
Type III Prototype: Acute post-streptococcal
glomerulonephritis
The reaction in the tissue is characterized by necrosis,
with deposits of “fibrinoid” and an infiltrate of PMNs.
glomerulus
Key difference from Type II Reaction: Reaction is to
immune complex deposition (bystander effect) rather
than to Ab bound to specific Ag on Tissue/cell.
Direct IF:
Detects Ab/Immune Complex Directly in biopsy
Patient’s tissue
Granular
pattern:
Type III IC
Acute
post-streptococcal
GN / SLE
Smooth
pattern:
Type II Ab
Goodpasture
Syndrome
Anti-Glomerular BM
(collagen IV)
Type 4 Hypersensitivity: Cell mediated
hypersensitivity
No Antibodies
CD4+ Th1/Th17: Delayed type hypersensitivity
(Granuloma, tuberculin reaction)
Activated macrophages / histiocytes
CD8+ CTL: Direct cell cytotoxity (graft rejection
& virus infection): Perforin/granzyme &
FAS/FASL
T cell–mediated (type IV) hypersensitivity reactions
Unlike other hypersentivity reactions, this reaction takes days
CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue
antigens by secreting cytokines that stimulate inflammation and activate
phagocytes, leading to tissue injury.
CD4+ TH17 cells contribute to inflammation by recruiting neutrophils (and,
to a lesser extent, monocytes).
Anti-CD4 Ab +
Classic Tuberculin Reaction (PPD): Reddening and induration
peaking at 24-72 hrs.
Perivascular infiltration of T cells (CD4+) and mononuclear
phagocytes “perivascular cuffing”
T cell–mediated (type IV) hypersensitivity reactions
CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells.
The Good:
Likely important in clearing of virally infected cells / intracellular
pathogens & tumor immune surveillance.
The Bad:
Important in mediating graft rejection and some autoimmune
diseases
Chronic Type IV reaction: Granuloma
Chronic Type IV reactions to persistant or
nondegradable Ags (TB and foreign bodies
(e.g. sutures) lead to granulomatous
inflammation.
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Systemic autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
REJECTION PROCESSES
Hyperacute:
Preformed antidonor antibody (ABO
incompatibility). RARE
Characterized by Ab: Complement in
endothelium
Gross: Pale/cyanotic non-functioning organ
Histology: Rapid thrombotic vasculitis w/ PMN
perivascular infiltrates/ischemic necrosis
Acute & Chronic Rejection
Acute Humoral Rejection: Type II Antibody Mediated
(Acute rejection vasculitis)
Can range from Necrotizing vasculitis (more acute-Ab mediated activation of
phagocytes) to less acute: Intimal thickening with inflammatory cells, foamy
macrophages and smooth muscle proliferation
Need B-cell depleting therapy:
(e.g. Rituximab (Rituxan®), humanized monoclonal anti-CD20, a B lymphocytespecific antigen).
Acute Cellular Rejection
Acute tubulointerstitial mononuclear infiltrate
T-cells
Chronic Rejection
Obliterative intimal fibrosis
“Graft ateriosclerosis”
Graft arteriosclerosis. The vascular lumen is replaced by an
accumulation of smooth muscle cells and connective tissue
(fibrosis) in the vessel intima.
Chronic Rejection:
Interstitial fibrosis
and tubular atrophy
Normal
Graft vs. Host Disease
Bone Marrow Transplants
Transplanted T-cells recognize recipient as “foreign”
and mount rejection response.
High mortality rate: sepsis
Bone marrow Trasplants:
High dose steroids & T-cell Depletion (anti-T cell
antibodies)
Immunosuppressed:
Irradiated Blood Products containing Leukocytes
Besides the icterus (yellow color,
jaundice) in this skin there is a
fine scaling rash in this patient
following bone marrow
transplantation with a 5 out of 6
antigen match. This is an
example of graft versus host
disease in which donor
lymphocytes attack host tissues.
Apoptosis and lymphocytic
infiltrates in epidermal/dermal
junction
GVHD
Cholestasis (brown bile) &
lymphocytic infiltrate
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Systemic autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
Mechanisms of Autoimmune Diseases: Genetics
(DR3/4, B27) & Environment play a role
A. Failure of peripheral tolerance.
B. Molecular mimicry -- cross reacting antibody (Rheumatic fever)
C. Breakdown of immune privilege (sperm and ocular antigens)
D. “Epitope spreading”: Immune response against initial “self” Ag
induces cell damage or alteration of macromolecules that reveals
additional epitopic sites that can be recognized – thus epitope
spreading:
1. Release of “hidden” intracellular Ags or Ags protected by large
protein/lipid complexes, or released by proteolysis of tertiary protein
folding.
2. Enzymatic modification in response to infection/inflammatory response
(e.g. Citrullinated proteins in RA) that alters normal structure.
Immune Mediated Inflammatory Diseases
1. Antibody or Immune Complex Mediated
Organ-specific (Covered in organ-specific chapters)
Autoimmune hemolytic anemias
Myasthenia gravis
Graves disease
Goodpasture syndrome
Systemic autoimmune diseases
Systemic lupus erythematosus (SLE)
2. Primarily T-cell mediated diseases (Autoantibodies present)
Organ-specific
Type I diabetes
Multiple sclerosis
Systemic autoimmune diseases
Rheumatoid arthritis
Systemic sclerosis (Scleroderma)
Sjogren syndrome
Immune Mediated Inflammatory Diseases
(Not covered – Not AI disease)
3. Chronic inflammatory disease / overly robust
immune responses
Inflammatory bowel diseases
Crohn’s disease
Ulcerative colitis
Psoriasis
IBD/Psoriasis: Anti-TNFa therapy (i.e. remicade) useful
Also useful for Rheumatoid Arthritis
Ab vs T-cell mediated AI disease not absolute
As expected, B-cell depletion therapy (anti-CD20; i.e. rituximab) is
useful in treating Ab-mediated diseases (i.e., SLE)
However, B-cell depletion therapy has also been shown to be useful in
treating T-cell dependent AI disease (i.e. Rheumatoid arthritis,
Sjogrens Syndrome). Thus, autoantibodies may play an important role
in these diseases.
Systemic AI Diseases
Systemic Lupus Erythematosis
Scleroderma: Systemic Sclerosis
Sjogren’s Syndrome
Mixed Connective Tissue Disease (MCTD)
SYSTEMIC LUPUS ERYTHEMATOSUS
1.
Systemic inflammatory disease mediated by immune complex
deposition in vascularized tissues. Chronic, remitting and relapsing,
febrile illness.
2.
Characteristic antinuclear antibodies: Positive ANA test: dsDNA,
RNA, ribonuleoprotein, histone proteins.
+ANA = HI SENSITIVITY
3.
Anti-dsDNA or Smith (Sm) Ag is virtually diagnostic of SLE.
+ Anti-dsDNA or Sm = HI SPECIFICITY
4.
Numerous Autoantibodies (over 120 described), tests for syphilis and
HIV may be false positive.
Systemic Lupus Erythematosus
Visceral lesions are caused by
DNA-anti-DNA complex deposits.
High titer anti-dsDNA = nephritis
(titers used to monitor therapy & disease
progression)
Anti-SS-A (Ro)/B (La): Maternal - fetal transfer = present in 90%
of mothers with neonatal lupus (heart block)
Anti-SS-A/B and neonatal lupus also seen with Sicca (Sjogrens)
Syndrome
Lupus Anticoagulant: Antiphospholipid Syndrome
(PROTHROMBOTIC STATE)
LUPUS NEPHRITIS: (Classification)
Class
Notes
I. Minimal
Mesangial
Normal Glomeruli - Light microscopy (LM). Immune complex (IC)
deposits seen only by electron microscopy & immunofluorescence
II. Mesangial
Proliferative
Matrix expansion with mesangial hypercellularity by LM.
III. Focal
Proliferative
Glomerulonephritis in < 50% of glomeruli (May involve all or portions of
each glomerulus). Crescents & fibrinoid necrosis may be present.
IV. Diffuse
Proliferative
As in class III, but involvement of ≥ 50% of glomeruli.
Advanced and often rapidly progressive to ESRD
V.Membranous
Thickened glomerular basement membrane without a hypercellular
glomerulus (non-proliferative).
High rate of nephrotic syndrome (protein loss & edema).
Tends to be more indolent
VI. Advanced
Sclerotic
≥ 90% of glomeruli sclerosed. No evidence of active glomerular disease.
End-stage renal disease
DNA:anti-DNA Deposition in Lupus Glomerulonephritis
1&2. Subepithelial deposition w/humps (1)
& spikes (2)
3. Subendothelial deposition
4. Mesangial deposition
5. Basement membrane
I.
Minimal Mesangial: Mesangial immune complex (IC)
deposits by electron microscopy (EM) or direct
immunofluorescence (DIF), not light microscopy (LM)
II. Mesangial: Granular mesangial IC deposits by LM
III. Focal Proliferative (FP): Mesangial/subendothelial IC deposits
IV. Diffuse proliferative (DP): Extensive Mesangial/subendothelial/subepithelial IC
deposits by LM (wire loops may be seen). If subepithelial extensive = combined class
IV & V.
V. Membranous (ME): Subepithelial +/- Mesangial & subendothelial. Wire loops may
be seen.
Proliferative GN
Proliferative GN: Lots of cells (not normal)
Remember the other
type III glomerular
disease:
Post-streptococcal
GN
IgG Direct IF “granular”
Normal Glomerulus
Proliferative GN
Glomerulus with segmental endocapillary proliferation
SLE: Glomerulonephritis with “wire loop” thickening of the
glomerular capillary basement membrane
(Extensive subendothelial IC deposits).
Wire loop
Normocellular GN
Membranous GN:
Silver stain best for detecting subepithelial deposition: Silver stains BM,
but not IC deposits. Interdigitating spikes (arrow) represent BM staining
as the BM wraps around IC deposits. Over time, BM will completely
cover the deposits with domes and markedly thickened, irregular BM.
Glomerular Sclerosis: Entire Bowman’s capsule space
is scarred over
Disorders Related to SLE
(anti-dsDNA rare)
• Discoid Lupus - affects skin only-erythematous,
scaly plaques, alopecia. Causes scarring
(characteristic dermoepidermal Ig). Systemic
symptoms uncommon.
• Subacute Cutaneous Lupus – tends to be more
widespread, superficial and non-scarring. Most
have mild systemic symptoms. Anti-SS-A/B Abs &
HLA-DR3 genotype common.
• Drug-induced lupus -- drug causes positive ANA,
but symptoms are mild and remit with drug
withdrawal (anti-histone Ab’s).
Rash in neonatal lupus:
Subacute cutaneous lupus
Cutaneous Lupus
Inflammation
necrosis
Edema
Avoid UV light!
Note + stained nuclei in
epidermis (ANAs)
Junctional
IgG (Direct IF)
(aka: Lupus Band Test)
Systemic AI Diseases
Systemic Lupus Erythematosis
Scleroderma: Systemic Sclerosis
Sjogren’s Syndrome
Mixed Connective Tissue Disease (MCTD)
Scleroderma or “Progressive” Systemic
Sclerosis
Systemic inflammatory disease marked by progressive
interstitial and perivascular fibrosis of skin and viscera.
Intimal proliferation (100% of digital arteries): Proliferation of
intimal cells, endothelial cells, and smooth muscle cells with
perivascular fibrosis.
Perivascular lymphocytic cuffing (CD4+ T-cells) is seen.
Fibrosis leads to:
Peripheral vascular disease
Renal hypertension / failure
Pulmonary HTN/fibrosis
Dysmotility syndromes (esophageal/gut)
CD4+ T-cell activation (unknown Ag trigger) with production of repair
or fibrogenic cytokines (e.g. TGFb). Alternatively, abnormal FB
responses may be involved: FB hyper-responsiveness to fibrogenic
cytokines or abnormal FB collagen production.
Skin: Increased dermal
collagen. Chronic inflammatory
cells are sparse with systemic
sclerosis, unlike SLE.
At high magnification, the
dermis is expanded by dense
collagenous fibrosis.
Subtypes of systemic sclerosis
1. Diffuse systemic sclerosis
Skin
Gastrointestinal tract
Renal (about 30%): Renal arterial intimal fibrosis leading
to malignant hypertension and renal infarcts.
Interstitial lung disease (30%–40%): Most common cause of death
Pulmonary hypertension - may be primary arterial hypertension
(small percentage) or secondary to interstitial lung disease
Myositis
Cardiac
Autoantibodies in diffuse disease:
Scl 70 antibodies (10-20%)—increased risk of interstitial pulmonary
fibrosis
RNA polymerases I, III—increased risk of renal disease, probably
cardiac disease
Subtypes of systemic sclerosis
2. Limited systemic sclerosis
Skin involvement of fingers, later hands, face, and feet
Raynaud phenomenon
Visceral disease less common and occurs late
Gastrointestinal involvement
Primary pulmonary hypertension (25%–50%)
Interstitial pulmonary fibrosis (10%)
Anticentromere antibodies (20-30%)—indicates
increased risk for pulmonary hypertension & CREST
CREST syndrome common: Calcinosis cutis, Raynaud phenomenon,
esophageal dysmotility, sclerodactyly, telangietasia
Microvascular intimal fibrosis and
subepithelial/submucosal fibrosis
Trichrome stain
submucosal fibrosis
Submucosal collagen deposition.
Such fibrosis can occur anywhere
in the gastrointestinal tract, but is
most common in the lower
esophagus, leading to the
esophageal dysmotility with
systemic sclerosis.
Intimal fibrosis
mucosa
Renal disease suggests diffuse
scleroderma in this patient with
hyperplastic arteriolosclerosis
and malignant hypertension
(blood pressure 300/150 mm Hg).
Systemic Sclerosis: Pulmonary Alveolitis
Inflammatory "alveolitis"
of scleroderma lung. Note
the irregular thickening of
alveolar walls by
inflammatory cells
(arrows), sometimes
making lymphoid
aggregates (LA).
◄ Pulmonary
Interstitial Fibrosis:
Alveolar walls are
distended by collagen
(arrows), fibroblasts,
and some chronic
inflammation (blue cells
here).
Pulmonary HTN:
Primarily vascular fibrosis
► Pulmonary artery in a
scleroderma patient with
pulmonary hypertension.
◄ Normal Pulmonary
Artery
Systemic AI Diseases
Systemic Lupus Erythematosis
Scleroderma: Systemic Sclerosis
Sjogren’s Syndrome
Mixed Connective Tissue Disease (MCTD)
Sjogren’s (Sicca) Syndrome:
Symptoms: keratoconjunctivitis &
siccaxerostomia
Laboratory: anti-SS-A / anti-SS-B
Physical Exam:
Mikulicz syndrome:
lacrimal and salivary
gland enlargement
Can also have babies with neonatal lupus
Salivary Gland: Sjogren’s Syndrome
Interstitial fibrosis
Mononuclear
infiltrate
Glandular
atrophy
-Extraglandular involvement (approx 30%): Pleuritis & pulmonary
interstitial fibrosis, synovitis, tubulointerstitial nephritis, skin,
peripheral neuropathy.
-Approx 40 x increased rate of B-cell marginal zone lymphomas
Systemic AI Diseases
Systemic Lupus Erythematosis
Scleroderma: Systemic Sclerosis
Sjogren’s Syndrome
Mixed Connective Tissue Disease (MCTD)
Mixed Connective Tissue
Disease
A mixture of SLE, RA, scleroderma, and
polymyositis.
Anti-snRNP
U1 ribonucleoprotein (U1-RNP)
Polymyositis: Inflammatory Myopathy
(Covered in Ch 27)
Disease
ANA
SLE
dsDNA
SS-B
histone
Sjogrens
Scleroderma
Specific Association
High titers = Nephritis
Neg. Assoc. w/ nephritis
Drug-induced Lupus
SS-A/B: Neonatal lupus
SS-A/SS-B
Congenital Heart Block/rash
ScI-70
centromere
Diffuse disease
CREST / Prim. Bil. Cirrhosis
Note: If anti-dsDNA or -Sm Ag is present, regardless of other
antibodies present = most likely SLE
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Systemic autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
PRIMARY IMMUNODEFICIENCY
SYNDROMES
(very rare to relatively common genetic disorders)
Defect of humoral immunity:
• X-linked agammaglobulinemia of Bruton (tyrosine kinase
deficiency)
• Common variable immunodeficiency
• Isolated IgA deficiency (related to CVI)
• X-linked Hyper IgM
Defect of Cell mediated immunity:
• DiGeorge’s syndrome (thymic hypoplasia)
• SCID
Types of Infection Associated with Immunodeficiencies
Pathogen
Type
T-Cell Defect
B-Cell Defect
Bacteria
Bacterial Sepsis
● Pyogenic bacteria
Streptococci
Staphylococci
Haemophilus
Viruses
● Cytomegalovirus
● Epstein-Barr Virus
● Severe Varicella
● Chronic Infections
with respiratory &
enteroviruses
Enteroviral encephalitis
Fungi &
Parasites
● Candida
● Pneumocystis
Severe intestinal
giardiasis
Special
Features
● Aggressive disease
with opportunistic
pathogens
● Failure to clear
infecions
● Recurrent
sinopulmonary
infections
● Sepsis
● Chronic meningitis
Granulocyte
Defect
Staphylococci
Pseudomonas
● Candida
● Nocardia
● Aspergillus
Complement
Defect
● Neisserial
infections
● Other
pyogenic
bacteria
infections
X-linked Agammaglobulinemia of Bruton
(tyrosine kinase deficiency (Btk))
 Defect in B-cell maturation and light chain rearrangement (cytoplasmic
heavy chain is produced, but no light chain)
 Onset after maternal IgG titer drops.
 Recurring sinopulmonary infections (almost always Haemophilus
influenzae, Streptococcus pneumoniae, or Staphylococcus aureus).
 Prone to meningoencephalitis with enteroviruses (No live polio vaccine)
and persistant Giardia protozoan infections also seen.
 High frequency of Autoimmune Disease
Common Variable Immunodeficiency
 Relatively common (Sporadic & Inherited forms). Males = Females
 Hypogammaglobulinemia (variable loss of Ig classes (can be only
IgG).
Symptoms usually less severe than those observed in Bruton’s
agammaglobulinemia.
 Defects detected in a small subset of inherited form of CVI:
• BAFF cytokine receptor mutation (B-cell survival & differentiation).
• ICOS: Protein homologous to CD28 and involved in T-cell activation and B-cell
interaction.
 Relatives have high frequency of selective IgA deficiency
 High frequency of AI disease and lymphoma
Isolated IgA Deficiency:
 Most common primary immunodeficiency disease
(1:600 of European descent).
 Familial and acquired (e.g. post-viral syndrome)
 Like CVI, defect in B-cell maturation to IgA-producing cells
(e.g. BAFF cytokine mutation also seen in CVI).
 Associated with mucosal infections (sinopulmonary, GI, UTI)
and high rates of atopy (i.e. allergic bronchitis) and autoimmune
disease.
 Anaphylactic reaction during transfusions (whole blood, plasma
containing IgA). Common Board question.
Hyper IgM Syndrome
Defect of B-cell class switching and maturation: Pyogenic
infections / pneumonia from intracellular pathogen:
Pneumocystis jiroveci
 70%: X-linked loss of CD40
ligand (CD154)
on T-cells
 Remaining: Autosomal
recessive – Mutations encoding
CD40 or the enzyme activationinduced deaminase (Enzyme
required for class switching)
T-cell antigen Recognition
and CD40 Co-stimulation
B-cell
Ag
Th-cell
CD40 CD40L
IFNg
IL-4
DiGeorge Syndrome:
Thymic Hypoplasia
 Chromosomal deletion syndrome (22q11 deletion
syndrome (Ch 5): Aplasia or hypoplasia of 3rd and 4th
pharyngeal pouch (Thymus and parathyroid) during
embryogenesis.
 Other associated abnormalities of aorta, congenital
heart disease and facial anomalies
 Failure of T-cell maturation (absent thymus) and
hypocalcemic seizures/tetany (absent parathyroid)
(usually cause for diagnosis in newborns)
Both Cellular & Humoral
Severe Combined Immunodeficiency (SCID)
“bubble baby”.
Severe bacterial, viral, fungal infections.
Thymus small and devoid of lymphocytes.
X-linked (most common)
Genetic loss of common gc-chain for
cytokine receptors (IL-2, IL-4, IL-7 etc).
IL-7: Lymphoid progenitor proliferation
Autosomal Recessive
Adenosine Deaminase (ADA)
JAK3 (gc chain signaling)
IL-7a receptor
MHC class II deficiency (“bare lymphocyte syndrome”)
ACQUIRED SECONDARY IMMUNODEFICIENCY SYNDROMES
(very common conditions)
•
AIDS
•
Cancer (e.g. myeloma)
•
Cancer treatment: (Bone marrow transplant)
radiation, chemotherapy
•
Aging: Most common immunodeficiency syndrome.
Decreased T-cell proliferative responses, blunted
cytokine response (IL-2), decreased circulating naive
T-cells (ThP). B and T-cell anergy
OBJECTIVES
Lecture 1:
• Review basic principles of cellular and humoral
immunity
• Immune tolerance
• Four types of hypersensitivity reactions
• Transplant / Graft rejection
Lecture 2:
• Systemic autoimmune diseases
• Immunodeficiency disorders
• Amyloidosis
AMYLOIDOSIS
One of the extracellular “hyaline”
accumulations
Amyloid deposition results from deposition of distinct
proteins (e.g. lambda light chains, b-amyloid protein)
which aggregate as b-pleated sheets secondary to
altered protein secondary or tertiary structure and are
resistant to proteolytic degradation.
Congo Red Birefringence
SYSTEMIC
PRIMARY AMYLOIDOSIS:
Amyloid (AL) Ig light chain fragments “Bence Jones protein”, synthesized in
copious excess by simply dysfunctional, or overtly malignant (multiple
myeloma) monoclonal plasma cells.
SECONDARY REACTIVE SYSTEMIC (AA):
Amyloid (AA) from serum amyloid associated (SAA) protein synthesized by liver
in response to inflammatory cytokines (e.g. IL-1). Associated with chronic
inflammatory diseases (e.g. Rheum. Arthritis)(Heroin “skin poppers”)(Also
Heriditary Familial Mediterranean Fever).
SECONDARY HEMODIALYSIS-ASSOCIATED (Ab2m):
Amyloid from b2 microglobulin (component of MHC class I receptor)
HEREDITARY AMYLOIDOSIS: Transthyretin (ATTR):
Neuropathic disease with pre-albumin (transthyretin) amyloid
SYSTEMIC DISEASE
Kidney: Nephrotic syndrome-End stage kidney
disease - Congo-Red birefringence in glomeruli.
Spleen (Splenomegaly): Splenic follicle
deposition (Sago)/Sinus deposition (lardaceous)
Liver (hepatomegaly)
Heart: CHF, conduction defects, restrictive
cardiomyopathy
Adrenals, thyroid, pituitary, GI tract
Localized Amyloidosis
 Alzheimers: Amyloid beta (Aβ) plaques from Amyloid
precursor protein (APP).
 Senile systemic amyloidosis: Systemic deposition of
transthyretin (ATTR)-biggest issue is restrictive
cardiomyopathy and conduction abnormalities.
Inherited: Mutant transthyretin (ATTR amyloid)
(4% African-Americans carriers) – Cardiac
mainly
 Endocrine amyloid (tumors, IDDM): Polypeptide
protein (e.g. calcitonin) or unique proteins that produce
microscopic lesions
Congo red stain of kidney biopsy.
Plane-polarized
birefringence
amyloid
Cardiac Amyloidosis
Cardiac muscle
Amyloid
Free Lambda LC
Direct IF: AL Amyloid
Liver
Amyloid
Congo Red
Tongue: Macroglossia
The End