Download Immunology

Pathobiology: Immunopathology (Bosch)
BRIEF REVIEW OF THE IMMUNE SYSTEM:

Innate (Natural) Immunity:
Skin and Mucosal Barriers
Phagocytes (PMNs and Macrophages): stimulated by microbial products and chemical mediators to destroy pathogens
o Mediators: C5a, C3b, thrombin, LTB4, PAF, TNF, IL-1, chemokines
o Process:

Margination (blood stasis)

Rolling (selectins and ligands)

Adhesion (integrins and ligands)

Transmigration (leukocyte adhesion molecules such as PECAM-1 and collagenases)

Chemotaxis (actin reorganization)

Activation and attachment (usually receptor-mediated)

Phagocytosis (formation of phagolysosome and degradation)
Natural Killer (NK) Cells: large granular lymphocytes
o Function:

Lyse Target Cells: virus infected cells, tumor cells
 Require NO prior sensitization*
 Killing regulated by balance between:
o Signals from activating receptors (stimulated by viral/stress-induced proteins)
o Signals from inhibitory receptors (engaged by normal levels of self-class I MHC)
Plasma Proteins:
o Complement cascade (activated by alternative and lectin pathways; classic pathway is part of adaptive)
o C-reactive protein
o Mannose-binding lectin

Adaptive (Specific) Immunity:
Components:
o Cell-Mediated Immunity: intracellular pathogens
o Humoral (Ab-Mediated) Immunity: extracellular microbes
T Lymphocytes:
o General Features:

2/3s of circulating lymphocytes are mature, naïve T cells

Attracted by chemokines to specific regions of lymphoid organs (ie. paracortex of LN)
o Production: occurs in the thymus

Unique TCR gene RARs occur resulting in mature T cells with antigen-specific TCRs

TCRs linked to molecular complexes (CD3 proteins, co-receptors CD4 or CD8) required for activation
o Activation: requires presentation of membrane-bound Ag in association with MHC PLUS interaction of costimulatory molecules on APCs and T cells

Results in secretion of cytokines, cell proliferation and differentiation into effector or memory cells
o Subtypes:

CD4+ (Helper) T Cells: CD4 co-receptor binds APCs class II MHC (self-class II MHC restricted); function
to secrete cytokines to modulate immune response
 TH1: secrete IL-2 and IFN-γ
o T cell proliferation, macrophage activation and Ab production
 TH2: secretes IL-4, IL-5 and IL-13
o Eosinophil activation and IgE synthesis
 Regulatory T Cells: suppress APCs or effector T cells by several mechanisms (release of
immunosuppressive factors, cell mediated regulation, cell lysis)
o Natural Regulatory T Cells (Tregs): CD4+, CD25+, Foxp3+ T cells

Also suppress autoreactive T cells
o Adaptive Regulatory T Cells: non-regulatory CD4+ T cells induced by inflammation

Upregulate CD25 expression in the periphery (ie. MALT)

-

CD8+ (Cytotoxic) T Cells: CD8 co-receptor binds class I MHC present on all cell types (self-class I MHC
restricted); primarily function to lyse cells
B Lymphocytes:
o General Features:

10-20% of circulating lymphocytes are B cells

Attracted by chemokines to specific regions of lymphoid organs (ie. cortex of LN, within lymphoid
follicles)
o Production: occurs in the bone marrow

Unique Ig gene RARs occur, leading to formation of mature B cells with Ag-specific BCRs made of Igs

BCRs linked to cell membrane proteins required for activation

Additional receptors play a role in B cell function as well
o Activation: results in differentiation to plasma cells (secrete Abs)
Dendritic Cells:
o Dendritic Cells (Interdigitating Dendritic Cells):

Location: widespread in epithelial surfaces and interstitium of tissues; may also be recruited to T cell
regions of lymphoid organs via a chemokine R

Function: present Ags (esp. proteins) to CD4+ T cells, promoting their activation
o Follicular Dendritic Cells:

Location: germinal centers of lymphoid follicles

Function: present Ags (bound to Abs and complement) to B cells, promoting their activation
Other Cell Types:
o Macrophages:

APCs for T cells

Effector cells for both cellular and humor immunity (ie. via phagocytosis)
o NK Cells:

Participate in ADCC (Ab dependent cell-mediated cytotoxicity)
Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) Complex:
General:
o Closely linked polymorphic genes on chromosome 6
o Major role to bind and present peptide fragments of foreign proteins to Ag-specific T cells
o Reactivity of T-cell immunity depends upon:

MHC molecule exposure during T-lymphocyte development

MHC genetic inheritance (ie. some immune disease associated with specific HLA alleles)
Class I MHC:
o General Features:

Located on the surface of all nucleated cells and platelets

Variable chain, containing the peptide-binding site, encoded by 3 genetic loci (HLA-A, HLA-B, HLA-C)
o Function:

Foreign cytoplasmic antigens (ie. viral proteins) lysed into short peptides in proteasomes

Peptides transported to ER, bind variable chain of new MHC class I molecules, and relocate to cell
surface

Present peptides to CD8+ T cells
Class II MHC:
o General Features:

Located on cell surface of APCs (dendritic cells, macrophages and B cells)

Expression can be induced on other cell types (ie. in response to IFN-γ)

2 variable chains (interaction between the 2 forms peptide binding site) encoded by 3 subregions of
the HLA-D genetic locus (HLA-DP, DQ and DR)
o Function:

Exogenous antigens are cleaved into peptides inside of intracellular vesicles

Bind newly synthesized MHC class II molecules within the vesicles, and relocated to the cell surface

Present peptides to CD4+ T cells
MECHANISM OF IMMUNOLOGIC INJURY (HYPERSENSITIVITY REACTIONS):

Type I Hypersensitivity (Anaphylactic Type):
Pathogenesis:
o Initial Antigen Exposure:

Antigen (allergen) presentation by dendritic cells to pre-TH2 cells

Activation of TH2 cells leading to:
 Differentiation of IgE-secreting B cells and IgE secretion (IL-4)
 Increased eosinophil longevity (IL-3, IL-5, GM-CSF)

IgE attaches to mast cells and basophils via Fc receptors
o Subsequent Antigen Exposure:

Above events PLUS Ag binding to IgE attached to mast cells and basophils

IgE cross-linking leading to mast cell/basophil activation and degranulation
 Release of Preformed (Primary) Mediators: leads to earliest manifestations
o Biogenic amines (histamine, adenosine)
o Chemotactic factors (ie. call in eosinophils)
o Enzymes (ie. tissue damage)
o Proteoglycans (metachromatic staining of mast cells/basohphils)
 Release of Newly Synthesized (Secondary) Mediators: leads to late response
o Activation of phospholipase A2 in mast cell phospholipid membranes

Arachidonic acid production:
 Leukotriene synthesis (5-lipoxygenase pathway)
 Prostaglandin D2 synthesis (cyclooxygenase pathway)

Platelet-activating factor (PAF) production
o Cytokine and chemokine secretion (ILs, TNF, GM-CSF)
Histopathologic Findings:
o Vascular Changes: vasodilation and increased vascular permeability  edema

Mediators: histamine, LTC4/D4, PAF
o Bronchial Smooth Muscle Contraction: leading to hyperplasia and increased thickness of the airway

Mediators: histamine, adenosine, LTC4/D4, prostaglandin D2, PAF
o Increased Glandular Secretions: both nasal and bronchial, leading to mucinous metaplasia

Mediators: histamine, prostaglandin D2
o Inflammatory Cell Infiltration: especially eosinophils and chronic inflammatory cells (produce additional
mediates that enhance and prolong the hypersensitivity reaction)

Mediators: eosinophil chemotactic factor, LTB4, PAF, TNF-α, ILs
o Mucosal Epithelial Injury: primarily due to inflammatory cells (exacerbates the problem)
Clinical Features:
o Localized erythema: leading to shock (vasodilation)
o Edema: hives, nasal and laryngeal edema (vascular permeability)
o Wheezing and airway constriction: due to bronchospasm
o Rhinorrhea and bronchial mucous plugs: increased glandular and mucinous secretions

Type II Hypersensitivity (Antibody Mediated):
Complement-Dependent Reactions:
o Pathogenesis:

Ab + Cell Surface or Tissue Ag: complement activation, formation of MAC, cell lysis and tissue injury

Ab + Cell Surface Ag: phagocytosis by inflammatory cells via Fc or C3b receptors (if complement fixed)
o Clinical Examples:

Autoimmune reactions to normal or altered blood cells: RBCs, WBCs, platelets

Alloimmune hemolysis: transfusion reactions, hemolytic disease of the newborn

Autoimmune blistering skin diseases:
 Example: pemphigus vulgaris (Abs to epidermal, intercellular cement substance)

Goodpasture Syndrome: Abs to glomerular and pulmonary basement membranes
-
-

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC):
o Pathogenesis:

Ab (IgG or IgE) + Cell Surface Ag: Ab binds to sensitized inflammatory cells via Fc portion (Fc receptors
on effector cells), leading to targeted cell death
 Important: NO phagocytosis or complement activation
o Examples:

Normal Host Immune Responses: to parasites and malignant cells
Antibody Mediated Cellular Dysfunction:
o Pathogenesis:

Ab + Cell Surface Receptor: leads to impaired cell function (NO CELL DEATH)*
o Examples:

Myasthenia Gravis: Abs to Ach receptors of skeletal muscle motor end plates (bind and block R, acting
as an antagonist)

Graves’ Disease: stimulatory Abs to TSH receptor of thyroid follicular epithelial cells (bind and activate
R, acting as an agonist)
Type III Hypersensitivity (Immune-Complex Mediated):
Pathogenesis:
o Immune Complex Formation: circulating Ab + Ag (fixed or circulating)

Nature of Causative Antigens (Fixed or Circulating):
 Exogenous (Foreign):
o Microbial Ags (bacterial, viral, fungal, parasitic)
o Drugs
o Animal sera
 Endogenous (Self):
o Nuclear Ags
o Immunoglobulins
o Ags of malignant cells

Antibody Production: differentiation of Ag-specific B cells and formation of complement fixing IgM,
IgG or IgA antibodies
o Immune Complex Deposition:

Local Immune Complex Disease (Arthus Reaction):
 Circulating Ab + localized Ag  in situ immune complex formation at antigenic tissue site

Systemic Immune Complex Disease (Acute Serum Sickness):
 Circulating Ab + Ag  circulating immune complexes and deposition within tissues
o Deposition dependent on immune complex and host factors:

Immune complex factors: size, charge, structure

Host factors: adequacy of immune complex clearance by phagocytes
o Frequent sites of tissue deposition:

Small/medium-sized blood vessels

Renal glomeruli

Joints

Skin
o Tissue Injury:

Complement Activation:
 C3a/C5a: anaphylatoxins causing vasodilation and increased vascular permeability, leading to
enhanced tissue deposition of immune complexes
 C3b: opsonin leading to enhanced phagocytosis of immune complexes and inflammatory cell
activation
 C5a: chemotactant that recruits acute inflammatory cells
 C5-9 (MAC): leads to cell lysis

-
-

Acute Inflammatory Cell Infiltration and Activation (PMNs and Macs):
 Release of additional vasoactive and chemotactant substances
 Release of proteolytic enzymes
 Release of oxygen-derived free radicals

Activation of the Coagulation System:
 Platelets
 Coagulation cascade
Pathologic Findings:
o General: usually characterized by an acute necrotizing vasculitis of small to medium-sized blood vessels
o Histologic Features:

Fibrinoid necrosis of vessel wall: necrosis due to MAC/inflammatory cell enzymes leads to endothelial
disruption and activation of coagulation system (deposition of fibrin)

Acute inflammatory cell infiltrate: due to chemotaxis

Edema and hemorrhage: of surrounding tissues

Vascular luminal thrombosis: leading to ischemic necrosis of tissue dependent on that vascular supply
o Immunofluorescent Microscopic Features of Involved Vessels: granular “lumpy-bumpy” pattern when using Abs
to Ig and complement components
o Electron Microscopic Features of Involved Vessels: presence of electron dense deposits (immune complexes)
Clinical Examples:
o Acute streptococcal glomerulonephritis
o Systemic lupus erythematosus (SLE)
o Polyarteritis nodosa (associated with HBV)
o Rheumatoid arthritis
Type IV Hypersensitivity:
Delayed Type Hypersensitivity:
o Pathogenesis:

Initial Antigen Exposure: Ag + class II MHC on APC leads to differentiation of CD4+ T cells to sensitized
TH1 cells

Subsequent Antigen Exposure:
 Activation and proliferation of previously sensitized memory TH1 cells (cytokine secretion)
o IL-2: amplifies T cell response
o TNFα: endothelial cell activation and production of more inflammatory mediators
o IFNγ: accumulation and activation of macrophages
 Activation of macrophages leads to enhanced Ag presentation, killing and cytokine secretion
o IL-12: differentiation and activation of TH1 cells
o PDGF and TGFβ: proliferation of fibroblasts
o Histopathologic Findings:

Initial: CD4+ TH1 cell infiltrate (perivascular and diffuse)

Later: collections of activated macrophages (granulomatous inflammation)
o Clinical Examples:

Tuberculosis and tuberculin skin test

Fungal infections

Contact dermatitis (ie. poison ivy)
Cytotoxic T Cell-Mediated Hypersensitivity:
o Pathogenesis:

Ag + class I MHC leads to sensitization of CD8+ T cells and apoptotic death of target cell
 Perforin-granzyme and Fas-Fas ligand mechanisms
o Clinical Examples:

Viral Infections

Tumor Immunity

Acute graft rejection
TRANSPLANT REJECTION:

Pathogenesis- Solid Organ Transplant Rejection:
T Cell-Mediated Response:
o Direct Pathway: may be more important for ACUTE cellular rejection

Graft Recognition (Paradoxical Mimicry):
 Foreign (mismatched) MHC molecules on graft’s (donor’s) APCs (ie. dendritic cells; within the
transplanted graft) recognized by recipient’s CD4+ and CD8+ T cells

Graft Rejection:
 CD8+ T Cell-Mediated Hypersensitivity: differentiation of sensitized CD8+ T cells (dependent
upon CD4+ cytokine secretion and induction of APC activation) leads to target cell apoptosis
 Delayed Type Hypersensitivity: proliferation/differentiation of sensitized CD4+ cells to TH1
cells leading to cytokine production (IL-2, TNFα, IFNγ)
o Macrophage activation
o Amplification of inflammatory response
o Indirect Pathway: may be more important for CHRONIC rejection

Graft Recognition: foreign (mismatch) MHC molecules processed and presented by recipient’s APCs to
recipient CD4+ T cells

Graft Rejection:
 Delayed Type Hypersensitivity
Antibody-Mediated Response (Rejection Vasculitis):
o Preformed recipient Abs against donor Ags:

Cause: prior sensitization due to previous transplants, blood transfusions, pregnancies etc.

Result: hyperacute rejection
o Induced recipient Abs against donor Ags:

Cause: graft recognition by either direct or indirect pathway above and activation of CD4+ cells

Result: acute humoral rejection
 Complement dependent cytotoxicity (CDC)
 ADCC

Pathology- Renal Transplant Rejection:
Hyperacute Rejection:
o Cause: preformed recipient Abs to donor Ags
o General:

Time Frame: minutes to hours after transplantation

Signs: discoloration and malfunction of kidney, requiring its removal
o Pathogenesis: immune complex formation on the renal transplant vascular endothelium leading to complement
activation

Edema: due to vasodilation and increased vascular permeability

Acute inflammatory cell infiltrate

Endothelial cell damage: leading to fibrinoid necrosis, hemorrhage and thrombosis

Tissue infarction
Acute Rejection:
o General:

Time Frame: days to weeks after transplant or a reduction in immunosuppression

Signs: increased serum creatinine, decreased urine output and development of renal failure
o Acute Cellular Rejection:

Pathogenesis: interstitial mononuclear inflammatory cell infiltrate (mostly activated CD4+ and CD8+ T
cells) that may injure tubules (tubulitis) and vascular endothelial cells (endothelitis and edema)

Treatment: increased immunosuppression
o Acute Humoral Rejection (Acute Rejection Vasculitis):

Pathogenesis:
 Tissue Infarction: due to vascular fibrinoid necrosis, acute inflammation and thrombosis (due
to complement activation)

Tissue Atrophy: due to vascular intimal thickening by foamy macrophages and proliferating
fibroblasts/SMCs (as a result of cytokine production)
Treatment: no real good treatment (usually lose the graft)



Chronic Rejection:
o Time Frame: years after transplantation
o Signs: slowly increasing serum creatinine levels
o Pathogenesis: vascular fibrosis, renal atrophy, interstitial fibrosis and mononuclear inflammatory cell infiltrate
o Treatment: NONE
Prevention and Treatment of Solid Organ Transplant Rejection:
HLA Matching
Immunosuppression:
o Calcineurin inhibitors (cyclosporine, tacrolimus) that block IL-2 production
o Corticosteroids
o Antiproliferative agents (azathioprine)
o Anti-T cell R antibodies
Induction of Immunological Tolerance: for example, by use of selective costimulator blockers to prevent T cell
sensitization
Allogenic Hematopoietic Stem Cell Transplantation:
General: usually, the recipient’s immune system is ablated prior to transplantation (ie. by irradiation)
Immunodeficiency: increased susceptibility to infections (ie. reactivation of latent CMV)
Transplant Rejection: mediated by recipient’s surviving T cells and NK cells
Graft-versus-host (GVH) Disease: both acute and chronic forms
o Pathogenesis: donor’s immunocompetent CD4+ and CD8+ T cells react against the recipients cells

This is important because it also has beneficial anti-rejection and graft-versus-tumor function

Basically, the graft is fighting you so you can’t reject it (allow it to fight the tumor)
o Major Affected Tissues:

Skin: maculopapular rash
 Acute: desquamation
 Chronic: dermal fibrosis

Mucosal Surfaces:
 GI Tract: N/V/D
 Eyes and mouth: dryness and irritation (chronic)

Liver: jaundice due to injured bile ducts

Lymphoid Organs: damage compounds the recipient’s immunodeficiency
 May occasionally lead to autoimmune complications
AUTOIMMUNE DISEASES:

Immunologic Self-Tolerance:
Central Tolerance: immature self-reactive t cells (thymus) and B cells (bone marrow) eliminated by apoptosis
o Imperfect mechanism due to incomplete self-Ag presentation and other factors
Peripheral Tolerance:
o Anergy: presentation of self-Ags to T cells

T cell anergy results due to:
 Lack of expression of co-stimulatory molecules
 Binding of inhibitory T cell receptors to co-stimulatory molecules

B cell anergy results due to lack of self-reactive T cell help
o Suppression: cytokine secretion by regulatory T cells (CD4+, CD25+) leading to suppression of autoreactivity
o Deletion (Activation-Induced Cell Death):

Repeated activation of Ag-specific T cells by self-Ags

Binding of Fas (widespread cellular expression) to FasL on activated T cells

Elimination of autoreactive T cells by apoptosis
o Antigen Sequestration: hidden self-Ags within certain immune-privileged tissues (testis, eyes, brain)

Pathogenesis: autoimmune disease results due to a LOSS OF SELF-TOLERANCE
Genetic Predisposition: usually polygenic
o Inheritance of various genes (ie. certain MHC alleles) increases susceptibility to autoimmune disorders
o Precise MOA generally unclear (although some examples of autoimmune diseases in which a single gene
mutation impairs specific modes of peripheral tolerance)
Environmental Factors (Infection):
o Initiation of Autoimmune Reaction:

Possible Causes:
 Microbial induced increased expression of costimulatory molecules on APCs
 Immunological cross-reaction with self-Ags (molecular mimicry)

Overall Result: activation of autoreactive lymphocytes (action amplified by cytokines produced by
infection)
o Persistence and Progression of Disease Process:

Tissue damage secondary to infection and/or autoimmune response

Release and alteration of self-Ags (ie. exposure to normally concealed epitopes through epitope
spreading)

Continuing lymphocyte activation
EXAMPLES OF SYSTEMIC AUTOIMMUNE DISORDERS:

Systemic Lupus Erythematosus (SLE):
General: relatively common, clinically heterogeneous, relapsing and remitting autoimmune disease affecting multiple
organ systems (esp. skin, kidneys, joints and serosal surfaces)
Epidemiology:
o Most commonly diagnosed in early adulthood
o More common in females (esp. during reproductive years)
o Racial differences (more frequent and severe in African American women)
Etiology: multifactorial*
o Genetic Susceptibility: increased disease frequency in family members of patients with SLE (esp. MZ twins)

Association between specific HLA alleles and production of certain autoAbs found in SLE
 Anti-dsDNA Abs
 Anti-Smith Ag Abs

Inherited deficiencies in early complement factors are found in a minority of patients with SLE
 May cause impaired clearance of immune complexes and/or apoptotic cells
o Environmental Triggers:

Levels of sex hormones

Administration of certain medications (ie. hydralazine)

Exposure to UV radiation
Pathogenesis:
o General:

Genetically predisposed individual exposed to an appropriate environmental trigger

Loss of self-tolerance and activation of autoreactive CD4+ T cells, leading to stimulation of self-Ag
specific B cells and production of autoAbs
 ANAs against nuclear components (dsDNA, Smith Ag, histones)
 Antiphosholipid Abs
 Abs to formed elements of blood (RBCs, WBCs, platelets)

AutoAbs result in immune-complex and Ab-mediated tissue damage
o Antinuclear Abs (ANAs): bind to exposed nuclear Ags, resulting in immune complex formation in small blood
vessels and a type III hypersensitivity reaction

Fixation of complement, acute inflammation and cell death
o Antiphospholipid Abs: bind to exposed epitopes of proteins complexed to phospholipids (type III HS)

Delayed coagulation in vitro: lupus anticoagulant Abs

Hypercoagulability in vivo: secondary antiphospholipid Ab syndrome
o
-
Antibodies to Formed Elements of the Blood: bind to RCBCs, platelets and/or WBCs (type II HS)

Causes opsonization and phagocytosis, resulting in anemia, thrombocytopenia and/or leukopenia
Anatomic Pathology:
o Small Arteries and Arterioles:

Fibrinoid necrosis and acute inflammation leads to fibrous scarring (multiple organs)

Non-inflammatory occlusion (thrombotic and/or fibrotic)
o Kidneys:

Glomeruli:
 Light Microscopy:
o Class I: minimal to no abnormalities
o Class II: mesangial lupus glomerulonephritis (expansion of mesangium due to
increased number of mesangial cells and matrix)
o Class III: focal proliferative glomerulonephritis (scattered glomeruli with increased
cellularity and occasional fibrinoid necrosis and thrombosis)
o Class IV: diffuse proliferative glomerulonephritis (majority of glomeruli wit increase
cellularity frequently accompanied by fibrinoid necrosis and thrombosis)

Most common and most severe*
o Class V: membranous glomerulopathy (widespread thickening of glomerular
capillaries- MAC pokes holes)
o Wire Loops: substantial thickening of the capillary walls that may be seen by LM
with extensive immune complex deposition
 Direct Immunofluorescent Microscopy:
o Granular pattern of fluorescence within mesangium (and possible the glomerular
capillary walls) using anti-Ig and anti-complement probes
 Electron Microscopy:
o Electron-dense immune complexes within the mesangium
o May also have deposition in the following places:

Subepithelium (between visceral epithelial cells and basement
membrane; class V membranous lesions)

Subendothelium (between the endothelial cells and the basement
membrane; class III and IV proliferative lesions)

Tubulointerstitium: immune complex deposits within the tubular basement membranes
o Skin:

General: erythematous rash most common (butterfly/malar rash on the face; exacerbated by exposure
to sunlight)

Light Microscopy:
 Edema and degeneration of the basal cells along the dermoepidermal junction
 Often accompanied by dermal vasculitis

Direct Immunofluorescent Microscopy:
 Granular pattern of fluorescence at the dermoepidermal junction using anti-Ig and anticomplement probes
 Occurs in both lesional AND non-lesional skin
o Joints: synovial inflammation without articular erosion
o Serosal Surfaces: acute fibrinous inflammation leading to chronic inflammation and fibrosis
o CV System:

Heart:
 Libman-Sacks Endocarditis (small vegetations present on either side of the leaflets of any
valve)
 Myocarditis
 Pericarditis

Coronary Arteries: accelerated atherosclerosis
o Lymphoid Organs (LNs, Spleen): follicular hyperplasia with an increased number of plasma cells
-
-
-
Clinical Pathology:
o Antinuclear Abs (ANAs):

Detection and Quantitation by Indirect Immunofluorescence:
 General:
o Sensitive but nonspecific test (ie. almost everyone with lupus will have a + test, but
many false +)
 Patterns of Nuclear Fluorescence with Positive ANA Tests:
o Homogenous (Diffuse) Pattern: common and non-specific

Abs to diverse nuclear constituents (DNA, histones etc.)
o Rim (Peripheral) Pattern: most specific for SLE

Abs to dsDNA
o Speckled Pattern: common and non-specific

Abs to various non-DNA nuclear components (Sm Ag, U1-RNP, SS-A, SS-B)
o Nucleolar Pattern: most commonly seen with systemic sclerosis

Abs to nucleolar RNA
o Centromere Pattern: most commonly seen with limited systemic sclerosis (CREST)

Specific ANA Characterization:
 Follow-up to a positive IF-ANA test
 Especially Abs to dsDNA and Smith (Sm) antigen
o Antiphospholipid Abs:

Prolonged aPTT due to lupus anticoagulant Abs

Anticardiolipin Abs (can lead to false + syphilis test)
o Antibodies to Formed Blood Elements:

Lead to anemia, thrombocytopenia and/or leukopenia
o Lupus Erythematous Cells (Hematoxylin Bodies):

PMNs or macrophages that have phagocytosed the nuclei of injured cells
Clinical Manifestations: variable*
o Chronic relapsing and remitting disorder with common signs and sypmtoms:

Fever/malaise, mala rash worsened by sun exposure, joint pain
o Lab abnormalities including the following (as well as those listed above):

Hematuria , RBC casts, proteinuria (related to renal involvement)

Decreased serum complement levels (related to immune complex formation)
o Treatment usually involves immunosuppression (results in increased susceptibility to infection)
Lupus Variants:
o Chronic Discoid Lupus Erythematosus (Scarring Dermatosis):

Generally only involves the skin (particularly areas exposed to sunlight- face, scalp)

Scaling skin plaques with raised, red borders

Microscopic Findings:
 Epidermal atrophy
 Vacuolar change of basal cells
 Follicular plugging
 Dermal chronic inflammation (lesional skin has similar Immunofluorescent findings to SLE)
o Subacute Cutaneous Lupus Erythematosus (Nonscarring Dermatosis):

Photosensitive erythematous rash (dominant feature)

Mild systemic manifestations often present as well

Positive ANAs (esp. anti-Ro/SS-A antibodies)
o Drug-Induced Lupus Erythematosus:

Due to a number of drugs (ie. hydralazine, procainamide)

Presence of positive ANAs much more common than clinical sx of SLE (esp. antihistone Abs)

Withdrawal of the drug leads to disease remission

Sjorgen Syndrome:
General: chronic autoimmune disorder affecting predominantly lacrimal and salivary glands
o Most commonly diagnosed in middle-aged women (50-60 years old)
o Forms:

Primary (sicca syndrome)

Secondary (associated with other autoimmune diseases, most often RA)
Etiology:
o Genetic: autoAb formation associated with specific HLA alleles
o Environmental Triggers: maybe certain viral infections
Pathogenesis:
o Genetically susceptible individual exposed to an environmental trigger
o Loss of self-tolerance and activation of autoreactive CD4+ T cells (to yet undefined Ags)
o Stimulation of self-Ag specific B cells and production of various autoAbs

Rheumatoid Factor

ANAs directed against ribonucleoprotein Ags (SS-A/Ro and SS-B/La)
o Immunologically-mediated damage, primary to the lacrimal and salivary glands
Anatomic Pathology:
o Exocrine Glands: esp. lacrimal and salivary glands

Lymphocytic and plasma cell infiltration

Ductal epithelial cell hyperplasia

Eventual glandular fibrosis and acinar atrophy
o Mucosal Surfaces: corneal, nasal, oral

Drying with secondary ulceration and inflammation
o Other Organs: may occasionally be involved

Example: renal tubulointerstitium
Clinical Pathology:
o Detection of AutoAbs:

Rheumatoid Factor

ANAs to two ribonucleoprotein Ags (SS-A/Ro and SS-B/La)
Clinical Course:
o Chronic Condition: characterized by dry eyes (keratoconjunctivitis sicca; results in blurred vision) and dry mouth
(xerostomia)

Other upper airway mucosal surfaces may also be affected

Other frequently occurring symptoms:
 Parotid gland enlargement
 Rheumatoid arthritis
 Lymphadenopathy
 Increased risk of B-cell lymphomas

Systemic Sclerosis (Scleroderma):
General: chronic disease characterized by excessive fibrosis
o Predominantly affects middle aged women (50-60 years old)
Classification:
o Diffuse Systemic Sclerosis (Scleroderma):

Rapidly progressive: initial involvement of extensive areas of the skin, followed by abnormalities in
multiple visceral organs
 GI tract, joints, kidneys, lungs, heart, skeletal muscles
o Limited Systemic Sclerosis (Scleroderma):

Slowly progressive: frequently confined to the skin of the face and distal upper extremities

CREST Syndrome: subset of limited scleroderma
 Calcinosis (C), Raynaud phenomenon (R), esophageal dysmotility (E), sclerodactyly (S) and
telangiectasia (T)
-
-
-
Etiology/Pathogenesis:
o Abnormal Activation of the Immune System:

Cell-Mediated Immunity:
 Inappropriate stimulation of Ag-specific CD4+ T cells
 Secretion of cytokines (including GFs for fibroblasts)
 Excessive collagen production

Humoral Immunity: due to presence of ANAs
 Anti-Scl 70: against DNA topoisomerase I (fairly specific for diffuse systemic sclerosis)
 Anticentromere Ab: predominantly found in CREST syndrome
o Microvascular Damage:

Persistent injury to the microvascular endothelium (possibly due to inflammatory cell mediators)

Platelet activation and release of growth factors for fibroblasts

Excessive collagen production leading to fibrosis (exacerbated by vascular luminal narrowing with
resultant tissue ischemia, which also stimulates fibrosis)
Anatomic Pathology:
o Skin: usually involvement of distal upper extremities (ie. hands) first, followed by the face, proximal upper
extremities and the upper trunk

Small vessel damage with luminal restriction, edema, collagen degeneration and lymphocytic infiltrates
within the dermis, leading to:
 Dermal fibrosis with deposition of dense collagen
 Epidermal atrophy
 Microvascular hyalinization

Overall results include:
 Calcifications (CREST syndrome)
 Ischemic ulcerations
 Autoamputation
o GI Tract:

Mucosal atrophy and collagenization of the wall (esp. the esophagus)

Results in dysmotility, GERD and malabsorption (if SI is involved)
o Joints:

Synovial inflammation and fibrosis (usually not joint destruction)
o Kidneys:

Arterial intimal cell proliferation and deposition of ECM (usually no involvement of the glomeruli)

Results in HTN and more severe vascular changes (ie. arteriolar fibrinoid necrosis and thrombosis)
o Lungs:

Pulmonary and interstitial fibrosis

Vascular abnormalities of pulomary HTN
o Heart:

Fibrosis of myocardium and its arterioles

Occasional pericarditis
o Skeletal Muscle:

Lymphocytic infiltration
Clinical Features:
o Range of Organ Involvement: limited to diffuse

Usually begins with prominent skin changes (ie. cutaneous fibrosis, Raynaud phenomenon)

Can progress to involve multiple other organs:
 GI Tract: dysphagia, GERD, malabsorption
 Kidneys: proteinuria, malignant HTN, renal failure
 Lungs or Heart: cardiac failure

Mixed Connective Tissue Disease:
General Characteristics:
o Overlapping features of:

SLE (fever, cytopenias, lymphoid hyperplasia)

Polymyositis

Rheumatoid arthritis

Systemic sclerosis (swelling of the hands, Raynaud phenomenon, esophageal dysmotility, pulmonary
interstitial fibrosis)
o High titers of anti-U1 RNP (ribonucleoprotein) antibodies
o Minimal renal disease
o Very good response to corticosteroids (fairly easily treated)
INHERITED (PRIMARY) IMMUNODEFICIENCIES:

General:
Heterogeneous Diseases: may affect specific immunity (ie. T and/or B cells) or nonspecific host defenses (ie. phagocytes or
complement)
Most Common: disorders of humoral immunity (IgA deficiency most common)
Presentation: usually as recurrent/chronic infections in infancy or young adulthood; may also have increased susceptibility
to certain malignancies (lymphomas) and autoimmune disorders
B-Cell Immunodeficiencies: lead to deficient Ab production, and infections with certain organisms
o Pyogenic bacteria (often encapsulated)
o Certain viruses (especially enteroviruses)
o Intestinal parasites (ie. giardia)
T-Cell Immunodeficiencies: lead to deficient cell mediated production, and infections with different organisms
o Viruses
o Fungi
o Intracellular bacteria
o Protozoa

Severe Combined Immunodeficiency Diseases (SCID):
Profound Deficiency of BOTH Cell-Mediated and Humoral Immunity: severe defects in T and B function
o Impaired T Cell Function: usually a greater deficiency

Abnormal T cell differentiation (bone marrow stem cell or thymic defect), OR

Abnormal T cell activation
o Impaired Humoral Immunity:

Bone marrow stem cell defect, OR

Non-functional B cells secondary to abnormal T cell function (more common)
Pathogenesis: heterogeneous group with many mechanisms for abnormal development/activation of both T and B cells
o X-Linked Recessive: most common (50-60%)

More common in young boys

Due to abnormal IL receptor protein
o Autosomal Recessive:

Abnormal receptor/signaling proteins

Impaired expression of MHC class II molecules (Bare Lymphocyte Syndrome)

PNP deficiency (purine metabolism)

Adenosine deaminase (ADA)deficiency (~50% of autosomal recessive SCID)
 ADA normally involved in metabolism of adenosine and deoxyadenosine, and is esp.
important in developing lymphocytes
 Deficiency leads to accumulation of alternative metabolites that inhibit DNA synthesis
 Results in cellular toxicity (particularly to developing T cells)
 One of the first disorders to be treated with gene therapy
-
-
-

Pathology: depends on underlying defect
o Anatomic:

Systemic Lymphoid Tissue: virtually absent or hypoplastic

Thymus: small, nondescended and lacking lymphoid cells (Hassall’s corpuscles decreased or fetal in
appearance)
o Clinical:

Severe Lymphopenia: decreased mature T and B cells (may occasionally have adequate numbers, but
they are non-functional)

Deficient Cell-Mediated Immunity:
 No lymphoproliferative response to mitogens or allogenic cells (in vitro)
 No DTH reaction or allograft rejection (in vivo)

Deficient Humoral Immunity:
 Scant IgG, absent IgM and IgA
 No Ab response to vaccination
Clinical Manifestations:
o General: failure to thrive and severe recurrent infections (usually die by 1 year of age if untreated)
o Infections:

Pyogenic bacteria (Pseudomonas, Streptococcus, Staphylococcus)

Fungi and protozoa (Candida, Pneumocystis jiroveci)

Viruses (CMV, VZV, HSV)

Viable attenuated vaccines (vaccinia, BCG, MMR, varicella zoster)
o Graft-versus-Host Disease:

Transplacental transfer of maternal T cells

Blood transfusion (must inactivated T cells by irradiating blood products)
Treatment: early allogenic stem cell transplant
o Full immunologic function can be achieved
o Good chance of a take (ie. no CMI for graft rejection), but high risk of GVH disease (donor sample needs to be
depleted of mature T cells)
DiGeorge Syndrome:
Selective Deficiency of T cells and T Cell-Mediated Immunity: B cells and T-independent Ab responses are normal
Pathogenesis:
o Defective development of 3rd and 4th pharyngeal pouches (normally give rise to thymus, parathyroid glands,
parafollicular cells of the thyroid, aortic arch and parts of the lips and ears)
o Majority due to 22q11 deletion
Pathology:
o Hypoplastic or Absent Thymus: leads to defective T cell maturation

Low normal lymphocyte count (absent or reduced T cells)
 NORMAL B cells

Paracortical areas of LNs and periarteriolar lymphoid sheaths of spleen depleted
 B cell regions and plasma cells are NORMAL

Deficient cell mediated immunity (no DTH reactions or graft rejection)
 NORMAL serum Ig levels, iso-agglutinins, and Ab response to most bacteria
o Absent or Rudimentary Parathyroid Glands:

Hypocalcemia resulting in tetany (first few days of life)
o Congenital Defects: of the heart and great vessels
o Facial Deformities
Infections: early onset
o Types: viral, fungal and mycobacterial

Viral Infections: required IFNs and cytotoxic T cells

Fungi: require activation of macrophages by IFNγ
Treatment: transplantation of fetal thymus or thymic epithelium (often not needed)

Bruton (X-Linked) Agammaglobulinemia:
Selective Deficiency of B Cells, Plasma Cells and Humoral Immunity: T cells and cell-mediated immunity is normal
Pathogenesis:
o Defect due to a block in maturation of pre-B cells to B cells
o X-linked recessive (males)
Pathology:
o Decreased/absent B cells in lymphoid tissue

NORMAL numbers of pre-B cells and T cells in marrow
o Germinal centers absent in LNs and spleen, tonsils poorly developed

Tissue T cells NORMAL
o Lack of plasma cells in tissue
o Virtual absence of serum Igs

NORMAL T cell functions (DTH and graft rejection)
Infections: severe recurrent infections beginning at 6-12 months (when maternal Igs become depleted)
o Pyogenic bacteria
o Certain viruses (esp. enteroviruses and hepatitis viruses)
o Giardia lamblia (intestinal parasite)
Treatment: periodic gamma globulin infusions (passive immunity)
Associated Disorders: increased frequency of arthritis and autoimmune diseases
o Examples: dermatomyositis, lupus-like disorder

Isolated IgA Deficiency:
Selective Deficiency of IgA: most common primary immunodeficiency
Pathogenesis:
o Defect due to block in differentiation of IgA B cells to plasma cells (retention of immature phenotype)
o Possible Causes:

Congenital (variable inheritance pattern)

Acquired (toxoplasmosis, viral infections, drug exposures)
Pathology:
o Absence of both serum and sIgA (normal levels of IgM and IgG)
o Normal number of IgA B cells, but express immature phenotype (surface IgM, IgD and IgA)
o Serum Abs to IgA (found in ~40% of patients)

May be susceptible to anaphylactic reaction when transfused with blood containing IgA
Infections:
o Frequently asymptomatic
o May have recurrent sinopulmonary infections and diarrhea (loss of mucosal defenses in respiratory, GI and GU
tracts due to loss of sIgA)
Associated Disorders: increased frequency of
o Respiratory allergies
o Celiac Disease
o Autoimmune disease (rheumatoid arthritis, lupus-like disease)

Common Variable Immunodeficiency Disease:
General: relatively common heterogeneous group of disorders
o Can be congenital (inconsistent inheritance pattern) or acquired
o Often diagnosed in teenagers or young adults
Common Variable= Hypogammaglobulinemia: usually all Igs (occasionally only affects IgG)
Pathogenesis: different subtypes
o Intrinsic B Cell Defect: usually present (B cells proliferate in response to Ag, but fail to differentiate into plasma
cells to produce Ab), AND/OR
o Immunoregulatory T Cell Disorder: deficient helper T cell function OR excessive T-suppressor cell activity
-
-
-
Features of Most Common Subtype:
o Normal number of circulating B cells
o Hyperplastic B cell areas (lymphoid follicles) in LNs, spleen and GI tract due to persistent Ag stimulation
o Plasma cells ABSENT
o Recurrent infections due to humoral deficiency

Pyogenic bacteria

Intestinal infections (Giardia and C.difficile)
o Presence of non-caseating granulomas (unknown cause)
Associated Disorders: increased frequency of
o Autoimmune diseases (rheumatoid arthritis, pernicious anemia, hemolytic anemia)
o Lymphoma
Treatment: periodic IV Ig therapy

Wiskott-Aldrich Syndrome:
Diagnostic Triad:
o Immunodeficiency (cellular and humoral)
o Thrombocytopenia (small platelets, bleeding issues)
o Eczema
Overall: will have recurrent infections, bleeding complications or malignancies that lead to an early death (6-8 years)
Pathogenesis:
o X-lined recessive defect in Wiskott-Aldrich syndrome protein (WASp)
o Seems to function in cytoskeletal actin polymerization
Pathology:
o Early On: lymphocyte count and thymus are NORMAL

Poor Ab response to polysaccharide Ag (with normal immune response to protein Ags)

Especially susceptible to infections with encapsulated pyogenic bacteria
o Later: progressive depletion of lymphocytes in the blood and T-cell (paracortical) areas of LNs, leading to variable
loss of cellular immunity

Also have a strange Ig profile: decreased IgM, normal IgG, increased IgA and IgE
Associated Disorders: increased frequency of
o Lymphoma
Treatment: stem cell transplant

Ataxia-Telangiectasia:
General: autosomal recessive multisystem disorder due to ATM gene defects and chromosomal instability
Characteristics:
o Progressive neurological dysfunction
o Cerebellar ataxia
o Oculocutaneous telangiectasia
o Abnormal sensitivity to X-rays (dysfunction of DNA repair)
o Impaired organ development (increased α-fetoprotein levels)
o Variable immunodeficiency
o Increased malignancies

Deficiencies of Cell Membrane Molecules/Receptors:
Leukocyte Adhesion Deficiencies: rare genetic deficiencies of leukocyte adhesion molecules
o Possible Causes:

Decreased expression of β2 subunit of integrins (CD18), OR

Decreased expression of receptor required for selectin binding
o Result: recurrent infections (bacterial and fungal), poor wound healing and periodontal disease

Impaired leukocyte adhesion to endothelium in inflammation, PMN aggregation and chemotaxis,
phagocytosis, lymphocyte-mediated cytotoxicity, and/or T and B cell interactions
-

Bare Lymphocyte Syndrome (Autosomal Recessive SCID): deficiency of MHC class I Ags on cell surface leading to failure of
Ag presentation to CD4+ T cells (as well as impaired development of these cells
o Result: immunodeficiency (both cellular and humoral)

Recurrent infections (bacterial, fungal, viral and protozoal)
Disorders of Nonspecific Host Defenses:
Chronic Granulomatous Disease (CGD): rare neutrophil disorder
o Pathogenesis: lack of respiratory burst with phagocytosis

Defective activation of membrane NADPH-oxidase: impaired production of superoxide anion during
phagocytosis, leading to impaiure H2O2 production in the phagolysosome and impaired H2O2-MPOhalide killing system

Inheritance:
 Most X-linked recessive: PMNs deficient in PMN cytochrome b
 The rest are autosomal recessive: other components of NADPH oxidase system affected
o Infections: can be fatal

Frequent and severe chronic bacterial infections with abscesses and granulomas of subQ tissue, LNs,
lungs, liver etc.

Catalase positive bacteria (S.aureus, Serratia, Salmonella, E.coli) and fungi (Aspergillus)
o Treatment: IFNγ
Chediak-Higashi Syndrome:
o Pathogenesis: rare disorder of defective lysosomal trafficking regulator protein

Autosomal recessive disease

Results in abnormal organelle synthesis, trafficking and fusion
o Clinicopathologic Features:

Generalized increased fusion of cytoplasmic granules:
 Leukocytes (esp. PMNs): enlarged lysosomes lead to neutropenia and impaired PMN
function
o Chemotaxis, phagolysosome formation, and bactericidal activity esp. impaired
o Leads to recurrent infections (esp. by pyogenic bacteria)
 NK Cells: decreased function
 Melanocytes: giant melanosomes leading to partial oculocutaneous albinism (due to melanin
trapping)
 Platelets: abnormal dense bodies (leads to mild bleeding tendency)

Progressive neurological dysfunction

Eventual accelerated phase: characterized by life-threatening lymphoproliferative infiltrates
Genetic Deficiencies of Complement:
o C1 (q,r,s), C2 and C4 Deficiency: autoimmune and immune complex diseases

Lupus like disorder

Glomerulonephritis
o C3 Deficiency: frequent and serious pyogenic bacterial infections
o C5-9 Deficiency: recurrent disseminated Neisseria infections