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DISEASES OF IMMUNITY
Raymond L. Konger, M.D.
Associate [email protected]
Robbins PathologicBasis of Disease, 8th Ed.Chapter 6
OBJECTIVES• 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
Lecture 1:
FIGURE 6-1 The principal classes of lymphocytes and their functions in adaptive immunity.
CD4+ Th Development
ThPIL-2
Th0
Ag:MHC IIAPC
Th1 Th2
IFN-IL-4, IL-5 IL-17, IL-22, IL-2, TNF- PMN / Monocyte
Chemokines
Treg
TGF-IL-10
Naive Uncommitted
IL-12/ IFN- FoxP3 (-/-)= AI disease
CD4+/CD25+
Th17
IL-4TGF-IL-23IL-6
TGF-
OBJECTIVES• 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
Lecture 1:
Central T-cell ToleranceCentral 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)
Immature APC:CD80/86 (B7.1/7.2) Low
Pathogen
Activated APC:High CD80/86 ( )
+ Ag presentation MHCI &II ( )
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) & AdhesionReceptors (e.g. ICAM-1)
Ag:MHCI & II processing
CD80/86
CD80/86 interaction with CD28 (T-Cells)
Is Critical
Initiation of Adaptive Immune Response by Professional APCs: Dendritic Cells
T-cell peripheral tolerance: CD80/86 (B7.1/7.2) co-stimulation
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 expressinhibitory B7 receptor,
CTLA-4 ((-/-) mice assoc. with
AI disease) Polymorphisms assoc.with human AI disease
TregIL-10
TGF-
CD-28CTLA-4
Immune privilege:eyes, testes, fetal trophoblast
APC maturation:Viral syndromes often
precede AI onset
FoxP3(-/-)
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
CD4+T-cell
B-cell Activation: Peripheral Tolerance
1. 2.
B-cell
B-cell
Ag
B-cell Antigen Recognition and BCR Clustering (Mature B-cell)
or TI-Antigens (e.g., LPS)
T-cell antigen Recognitionand CD40 Co-stimulation(Naïve B-cell)
Ag
Ag
IFN-IL-4, IL-2
C3bCD21
EBV
B-cell class switch &Proliferation & Affinity Maturation
Ag
B-cellCD40 CD40L
MHC-II / TCR
MHC-II upregulation
Ab production
C3b
T-cell independent antigens:(e.g. Pokeweed mitogen &
Carbohydrate antigens)Induce low affinity IgM
and no memory cells
OBJECTIVES• 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
Lecture 1:
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, PAFCysLT1 receptor antagonists: zafirlukast (Accolate),montelukast (Singulair). 5-LO inhibitors: Zileuton (Zyflow)
Secondary Mediators (Cytokines)TNFIL-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.
Fatal acute laryngeal edema during an anaphylactic reaction to penicillin.
Extreme Early Response:Anaphylaxis
Basement membrane thickening
Inflammation with eosinophilsAlso: CD4+/Th2 NK-T cells
Mucus Plug
Asthma: Tissue Remodeling
Type 2 Hypersensitivity: Antibody-Mediated Reactions
In all cases: Immune reaction against
Ab/complement bound to cell or tissue
Target Cell
+ Ab
ComplementC5-9
MembraneAttack
Complex
Osmotic Lysis
C3bC3b
C3bReceptor
FcReceptor
Macrophage
Phagocytosis
OpsonizedCell
Type II: Cytotoxic Antibody Mediated
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.
Antibody has naturalligand activity
(Graves Disease)
Antibody has naturalligand blocking
activity(Myasthenia gravis)
Type II: Antireceptor antibodies
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
FB
Aschoff GiantCell Lymphocyte
Aschoff Bodies:Hallmark of Rheumatic
FeverGranulomatous lesions that
follow necrosis/degenerative phase and precedes fibrosis
(Found in only a smallsubset of patients)
Anitschkow cell
Phase 1: Formation of immune complexes in the circulation
Type III: Immune Complex
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
The reaction in the tissue is characterized by necrosis, with deposits of “fibrinoid” and an infiltrate of PMNs.
glomerulus
Type III Prototype: Acute post-streptococcal glomerulonephritis
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
Goodpasture Syndrome
Anti-Glomerular BM (collagen IV)
Granular pattern:
Type III IC
Smooth pattern:
Type II Ab
Acute post-streptococcal
GN / SLE
Patient’s tissue
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
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).
T cell–mediated (type IV) hypersensitivity reactions
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”
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
T cell–mediated (type IV) hypersensitivity reactions
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• 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
Lecture 1:
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 proliferationNeed B-cell depleting therapy:
(e.g. Rituximab (Rituxan®), humanized monoclonal anti-CD20, a B lymphocyte-specific antigen).
Acute Cellular RejectionAcute tubulointerstitial mononuclear infiltrate
T-cells
Chronic RejectionObliterative 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 DiseaseBone 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
Cholestasis (brown bile) & lymphocytic infiltrate
GVHD
OBJECTIVES• 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
Lecture 1:
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 anemiasMyasthenia gravisGraves diseaseGoodpasture syndrome
Systemic autoimmune diseasesSystemic lupus erythematosus (SLE)
2. Primarily T-cell mediated diseases (Autoantibodies present)
Organ-specificType I diabetesMultiple sclerosis
Systemic autoimmune diseasesRheumatoid arthritisSystemic sclerosis (Scleroderma)Sjogren syndrome
Immune Mediated Inflammatory Diseases(Not covered – Not AI disease)
3. Chronic inflammatory disease / overly robust immune responses
Inflammatory bowel diseasesCrohn’s diseaseUlcerative colitis
Psoriasis
IBD/Psoriasis: Anti-TNF therapy (i.e. remicade) usefulAlso 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 ErythematosisScleroderma: Systemic Sclerosis
Sjogren’s SyndromeMixed 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.
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
Systemic Lupus Erythematosus
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 deposition5. 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
Remember the other type III
glomerular disease:Post-streptococcal
GN
Proliferative GN: Lots of cells (not normal)
IgG Direct IF “granular”Normal Glomerulus
Glomerulus with segmental endocapillary proliferation
Proliferative GN
SLE: Glomerulonephritis with “wire loop” thickening of the glomerular capillary basement membrane
(Extensive subendothelial IC deposits).
Wire loop
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.
Normocellular GN
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).
JunctionalIgG (Direct IF)
(aka: Lupus Band Test)
InflammationnecrosisEdema
Avoid UV light!
Cutaneous Lupus
Note + stained nuclei in epidermis (ANAs)
Systemic AI Diseases
Systemic Lupus ErythematosisScleroderma: Systemic Sclerosis
Sjogren’s SyndromeMixed 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 diseaseRenal hypertension / failure
Pulmonary HTN/fibrosisDysmotility syndromes (esophageal/gut)
CD4+ T-cell activation (unknown Ag trigger) with production of repair or fibrogenic cytokines (e.g. TGF). Alternatively, abnormal FB responses may be involved: FB hyper-responsiveness to fibrogenic cytokines or abnormal FB collagen production.
At high magnification, the dermis is expanded by dense
collagenous fibrosis.
Skin: Increased dermal collagen. Chronic inflammatory
cells are sparse with systemic sclerosis, unlike SLE.
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
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.submucosal fibrosis
Trichrome stain
Renal disease suggests diffuse scleroderma in this patient with hyperplastic arteriolosclerosis and malignant hypertension
(blood pressure 300/150 mm Hg).
mucosaIntimal fibrosis
Microvascular intimal fibrosis and subepithelial/submucosal fibrosis
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 ErythematosisScleroderma: Systemic Sclerosis
Sjogren’s SyndromeMixed 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
Mononuclear infiltrate
Interstitial fibrosis
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 ErythematosisScleroderma: Systemic Sclerosis
Sjogren’s SyndromeMixed Connective Tissue Disease (MCTD)
Mixed Connective Tissue DiseaseA mixture of SLE, RA, scleroderma, and polymyositis.
Anti-snRNP
U1 ribonucleoprotein (U1-RNP)
Polymyositis: Inflammatory Myopathy
(Covered in Ch 27)
Disease ANA Specific Association
SLE
Sjogrens
dsDNASS-B
histone
High titers = NephritisNeg. Assoc. w/ nephritisDrug-induced Lupus
SS-A/SS-B
Scleroderma ScI-70centromere
Diffuse diseaseCREST / Prim. Bil. Cirrhosis
Note: If anti-dsDNA or -Sm Ag is present, regardless of other antibodies present = most likely SLE
SS-A/B: Neonatal lupusCongenital Heart Block/rash
OBJECTIVES• 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
Lecture 1:
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 ImmunodeficienciesPathogen
TypeT-Cell Defect B-Cell Defect Granulocyte
DefectComplement
Defect
Bacteria Bacterial Sepsis ● Pyogenic bacteria Streptococci Staphylococci Haemophilus
StaphylococciPseudomonas
● Neisserial infections● Other pyogenic bacteria infections
Viruses ● Cytomegalovirus ● Epstein-Barr Virus● Severe Varicella● Chronic Infections with respiratory & enteroviruses
Enteroviral encephalitis
Fungi & Parasites
● Candida● Pneumocystis
Severe intestinal giardiasis
● Candida● Nocardia● Aspergillus
Special Features
● Aggressive disease with opportunistic pathogens ● Failure to clear infecions
● Recurrent sinopulmonary infections● Sepsis● Chronic meningitis
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
70%: X-linked loss of CD40 ligand (CD154)on T-cells
Remaining: Autosomal recessive – Mutations encoding CD40 or the enzyme activation-induced deaminase (Enzyme required for class switching)
Th-cellB-cell
T-cell antigen Recognitionand CD40 Co-stimulation
Ag
CD40 CD40L
IFN-
IL-4
Defect of B-cell class switching and maturation: Pyogenic infections / pneumonia from intracellular pathogen: Pneumocystis jiroveci
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)
Severe Combined Immunodeficiency (SCID) “bubble baby”.
Severe bacterial, viral, fungal infections. Thymus small and devoid of lymphocytes.
X-linked (most common)
Autosomal Recessive
Genetic loss of common c-chain for cytokine receptors (IL-2, IL-4, IL-7 etc).IL-7: Lymphoid progenitor proliferation
Adenosine Deaminase (ADA) JAK3 (c chain signaling)
IL-7 receptorMHC class II deficiency (“bare lymphocyte syndrome”)
Both Cellular & Humoral
ACQUIRED SECONDARY IMMUNO- DEFICIENCY 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• 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
Lecture 1:
AMYLOIDOSISOne of the extracellular “hyaline”
accumulations
Amyloid deposition results from deposition of distinct proteins (e.g. lambda light chains, -amyloid protein)
which aggregate as -pleated sheets secondary to altered protein secondary or tertiary structure and are
resistant to proteolytic degradation.
Congo Red Birefringence
SYSTEMICPRIMARY 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 2 microglobulin (component of MHC class I receptor)
HEREDITARY AMYLOIDOSIS: Transthyretin (ATTR): Neuropathic disease with pre-albumin (transthyretin) amyloid
SYSTEMIC DISEASEKidney: 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.
amyloid
Plane-polarizedbirefringence
Cardiac Amyloidosis
Cardiac muscle
Amyloid
Free Lambda LCDirect IF: AL Amyloid
Liver
Amyloid
Congo RedTongue: Macroglossia
The End
