The Normal Immune Response
Innate immunity
- leukocytes recognize pathogen assoc. molecular
patterns by pattern recognition receptors
o ex. = toll-like receptors (TLRs)
- TLRs signal activation of NF-κB  turns on production
of cytokines & proteins  stimulate microbicidal
activities of phagocytes & other cells
- epithelial provide mechanical and also chemical
barriers (anti-microbial defensin)
Adaptive immunity
- lymphocytes and their products (antibodies)
- humoral
o protects from extracellular microbes & toxins
o mediated by B lymphocytes & products
- cell-mediated
o defense against intracellular microbes
o T lymphocytes
Cells of the immune system
T lymphocytes
- develop from precursors in the thymus
- mature T cells are in the blood and T cell zones of
peripheral lymphoid organs
- 60-70% of lymphocytes
- recognizes antigens by antigen-specific TCR
- TCR
o made of α and β chain
o each chain has variable & constant region
o αβ TCR recognizes peptide antigens that are
displayed by MHC molecules on APCs
o ensures only cell-assoc. antigens are seen by T
cells
- during T cell development in thymus, TCR genes
rearrange to form many diff. combos
- RAG-1 and RAG-2
o recombinance activating genes
o the enzyme produced by these genes mediate
rearrangement of antigen receptor genes in
developing lymphocytes
o inherited defects in RAG proteins  failure to
generate mature lymphocytes
- only T cells contain rearranged TCR genes
- presence of rearranged TCR genes is marker of Tlineage cells
- analysis of antigen receptor gene rearrangements can
detect lymphoid tumors
o polyclonal T cell proliferations = non-neoplastic
o monoclonal T cell proliferations = neoplastic
- TCR complex
o CD3 complex and the ζ chain dimer
 invariant in all T cells
 involved in transduction of signals into T
cell after TCR binds antigen
o along with TCR, forms TCR complex
- γδ T cells
o small subset of T cells that don't require MHC
proteins
o aggregate at epithelial surfaces (skin & mucosa
of GI and UG tracts)
- coreceptors (CD4 and CD8)
o CD4 T cells = cytokine-secreting helper cells
that help macrophages & B cells combat inf.;
bind to MHC II
o CD8 T cells = CTL (killer T cells) that destroy
host cells harboring microbes; bind to MHC I
o bind to MHC & initiates signals to activate T
cells
B lymphocytes
- develop from precursors in bone marrow
- present in peripheral lymphoid tissues (lymph nodes,
spleen, MALT)
- recognize antigen via B-cell antigen receptor complex
- IgM and IgD are membrane bound antibodies
- also have RAG-mediated rearrangements of Ig genes
- after stimulation by antigen & other signals, B cells 
plasma cells that secrete Abs
- Igα and Igβ are essential for signal transduction thru
the antigen receptor
- B cells also express complement receptors, Fc
receptors, and CD40
- type 2 complement receptor CR2 or CD21 is the
receptor for EBV
Dendritic cells
- most important APCs for initiating 1 T cell responses
against protein antigens
- located under epithelia & interstitia of all tissues
- Langerhans cells – immature dendritic cells in the
epidermis
- express many receptors for capturing microbes (TLRs
& mannose receptors)
- in response to microbes, they are recruited to T cell
zones of lymphoid organs where they are ideally
located to present antigens to T cells
- express high lvls of molecules needed for presenting
antigens to & activating CD4+ T cells
- follicular dendritic cell
o in germinal centers of lymphoid follicles in
spleen & lymph nodes
o have Fc receptors for IgG & C3b
o trap antigen bound to antibodies or
complement proteins
Macrophages
- process phagocytosed microbes & present antigen to T
cells
- T cells activate macrophages & enhance their ability to
kill ingested microbes
- phagocytose & destroy microbes opsonized by IgG or
C3b
NK cells
- 10-15% of peripheral blood lymphocytes
- contain abundant azurophilic granules
- aka large granular lymphocytes
- can kill a variety of infected and tumor cells
- CD16 & CD56 are surface molecules on NK cells
o CD16 = Fc receptor for IgG; allows NK cells to
lyse IgG coated target cells (anti-bodydependent cell-mediated cytotoxicity, ADCC)
- NKG2D receptors are activating receptors that
recognize surface molecules that are induced by
various kinds of stress (infection & DNA damage)
- NK cell inhibitory receptors recognize self-class I MHC
molecules expressed on all healthy cells & prevent
activation
- secrete cytokines (IFN-γ) which activate macrophages
to destroy ingested microbes
- IL-2 & IL-15 – stimulate prolif. of NK cells
- IL-12 – activate killing & secretion of IFN-γ
Tissues of the immune system
Generative lymphoid organs
- thymus – T cell development
- bone marrow – where blood cells & B lymphocyte
mature
Peripheral lymphoid organs
- lymph nodes, spleen, mucosal & cutaneous lymphoid
tissues
- 2 mucosal lymphoid tissues:
o pharyngeal tonsils
o Peyer’s patches of intestine
- T cells and B cells segregated into diff. regions within
peripheral lymphoid organs:
o B cells – in follicles around periphery or cortex
of each node
 B cells recently responded to an antigen
may have germinal center in the follicle
center
o T cells – in the paracortex, adjacent to follicles
o follicles – contain follicular dendritic cells
involved in activation of B cells
o paracortex – contain dendritic cells that present
antigens to T cells
o Spleen – T cells are conc. in periarteriolar
lymphoid sheaths surrounding small arterioles;
B cells reside in follicles
Lymphocyte recirculation
- effector T cells circulate to locate and eliminate
microbes
- plasma cells remain in lymphoid organs and secrete
Abs that can be carried to distant tissues
- naïve T cells exit the thymus & migrate to lymph nodes
- they enter T cell zones thru specialized postcapillary
venules (high endothelial venules, HEVs)
- if the T cell encounters an antigen that it recognizes, it
becomes activated and leave the lymph nodes to enter
circulation and migrate to the inf. site
MHC molecules
- display peptide fragments of proteins for recognition
by antigen-specific T cells
- encoded on chromosome 6, MHC or HLA complex
- class I MHC
o expressed on all nucleated cells & platelets
o encoded by HLA-A, HLA-B, HLA-C
o display peptides derived from proteins (viral
antigens located in the cytoplasm and usually
produced in the cell)
o recognized by CD8+ T cells
o CD8+ T cells recognize peptides produced by
cytoplasmic microbes (viruses) or tumors
o CD8+ T cells are class I MHC-restricted
- class II MHC
o encoded on HLA-D; has 3 subregions (HLA-DP,
HLA-DQ, HLA-DR)
o present antigens that are internalized in vesicles;
typically from extracellular microbes
o recognized by CD4+ T cells
o class II MHC mainly expressed on cells that
present ingested antigens & respond to T-cell
help (macrophages, B lymphocytes, dendritic
cells)
- combo of HLA alleles in each person = HLA haplotype
HLA & disease association
- inflammatory diseases
o HLA-B27
o ankylosing spondylitis
o postinfectious arthropathies
- autoimmune diseases
o HLA-DR
o autoimmune endocrinopathies
o RA = DR4
o chronic active hepatitis = DR3
o 1 Sjögren syndrome = DR3
o type 1 DM = DR3, DR4, DR3/DR4
- inherited errors of metab.
o 21-hydroxylas deficiency = HLA-BW47
o hereditary hemochromatosis = HLA-A
Cytokines
- short-acting secreted mediators
- interleukins = molecularly defined cytokines; mediate
communications btwn leukocytes
- cytokines of innate immunity
o produced rapidly in response to microbes
o made by macrophages, dendritic cells. NK cells
o mediate inflammation & anti-viral defense
o TNF, IL-1, IL-12, type I IFN, IFN-γ, chemokines
- cytokines of adaptive immune responses
o made by CD4+ cells
o made in response to antigen
o promote lymphocyte prolif. & differentiation to
activate effector cells
o IL-2, IL-4, IL-5, IL-17, IFN-γ
- hematopoiesis stimulation
o colony-stimulating factors
o stimulate formation of blood cell colonies from
bone marrow progenitors
o  leukocyte numbers during immune &
inflammatory responses
Overview of lymphocyte activation
Display & recognition of antigens
- clonal selection hypothesis = antigen-specific clones of
lymphocytes develop before & independent of
exposure to antigen
- as antigens are being recognized by T & B cells,
microbes elicit an innate response
- in immunizations, antigen is given w/ an adjuvant to
induce innate response
- during innate response, microbe activates APCs to
express costimulators & secrete cytokines that
stimulate prolif. & differentiation of T cells
Cell-mediated immunity: activation of T cells and
elimination of intracellular microbes
- one of the earliest responses of CD4+ T cells =
secretion of IL-2 & expression of high-affinity
receptors for IL-2
o IL-2 = GF that stimulate their prolif.   in # of
antigen specific lymphocytes
- functions of helper T cells are mediated by combined
actions of CD40L + cytokines
- when CD4+ T cells recognize antigens being displayed
by macrophages or B cells, T cells express CD40L 
engage CD40 on macrophage or B cells and activate
them
- some progeny of expanded T cells differentiate into
effector cells that secrete diff. sets of cytokines (have
diff. functions)
o TH1
 secrete IFN-γ (macrophage activator)
 IFN-γ + CD40 mediated activation 
induction of microbicidal substances in
macrophages  destruction of ingested
microbes
o TH2
 secrete IL-4 (stimulate B cells to  IgEsecreting plasma cells)
 secrete IL-5 (activate eosinophils)
 eosinophils & mast cells bind IgE coated
microbes (helminths)
o TH17
 secrete IL-17
 powerful recruiters of neutrophils &
monocytes
 play major roles in inflammatory dz
Humoral immunity: activation of B lymphocytes &
elimination of extracellular microbes
- upon activation, B cells prolif. & differentiate into
plasma cells that secrete Abs
- full B cell response to protein antigens require help
from CD4+ cells
- B cells ingest protein antigens into vesicles degrade
them  display peptides bound to MHC molecules for
recognition by helper T cells  helper T cells express
CD40L + secrete cytokines  activate B cells
- polysaccharide & lipids stimulate secretion of mainly
IgM
- protein antigens (thru CD40L + cytokine-mediated
helper T cell actions) stimulate secretion of IgG, IgA,
IgE
- IFN-γ and IL-4 induce isotype switching
- affinity maturation = helper T cells stimulate
production of Abs w/ higher affinities for antigen
- neutrophils & macrophages have receptors for the Fc
tails of IgG  phagocytosis
- IgG and IgM activate complement system
- IgA = mucosal epithelia
- IgG = crosses placental barrier to protect baby
- IgE = kill parasites
- half-life of IgE = 2 weeks
Hypersensitivity and autoimmune disorders
Mechanisms of hypersensitivity reactions
Immediate (Type I) hypersensitivity
- rapid rxn within mins after combo of antigen + Ab
bound to mast cells in previously sensitized
- allergies
- may be systemic or local
- 2 phases:
o immediate rxn
 5-30 mins after exposure to allergen
 subside in 60 mins
 vasodilation, vascular leakage, smooth
muscle spasm or glandular secretions
o late-phase rxn
 2-24 hrs later w/o exposure to allergen
 lasts for several days
 infiltration of tissues w/ eosinophils,
neutrophils, basophils, monocytes, CD4+
cells, tissue destruction, mucosal epithelial
cell damage
- most rxns mediated by IgE Ab-dependent activation of
mast cells & other leukocytes
- mast cells
o bone marrow derived
o many near BV, nerve, subepithelial tissue
o cytoplasmic granules w/ many mediators
o activated by cross-linking of high-affinity IgE Fc
receptors
o also triggered by:
 C5a & C3a (anaphylatoxins)
o other secretagogues: IL-8, codeine, morphine,
adenosine, bee venom, physical stimuli
- basophils
o have surface IgE Fc receptors
o have cytoplasmic granules
o circulate in blood in small #s
- TH2 cells
o play central role in initiation & propagation of
type I hypersensitivity rxn
o stimulate IgE prod. & promote inflammation
o newly formed TH2 cells after activation by
exposure to antigen secrete cytokines
o IL-4: acts on B cells to stimulate class switch to
IgE; promotes development of new TH2 cells
o IL-5: help develop & activate eosinophils
o IL-13: enhances IgE production; enhances
mucus secretion
o secrete chemokines to attract more TH2 cells to
rxn site
- FcεRI = high affinity receptor for Fc portion if IgE
o antigens bind to IgE  cross links adjacent IgE
 bridging of Fcε receptor  activate signal
transduction  discharge of preformed
mediators from granules  de novo synthesis &
release of 2 mediators (lipid products,
cytokines)
- preformed mediators
o vasoactive amines (histamine – causes smooth
m. contraction,  vascular permeability, 
mucus secretions)
o enzymes (neutral proteases & acid hydrolases)
o proteoglycans (heparin, chondroitin sulfate)
- lipid mediators
o activate phospholipase A2
o leukotrienes (C4 & D4; most potent vasoactive &
spasmogenic agents known)
o prostaglandin D2 (causes intense bronchospasm
and  mucus secretion)
o platelet-activating factor (causes platelet
aggregation, release of histamine,
bronchospasm,  vascular permeability, and
vasodilation)
- cytokines
o TNF, IL-1, chemokines prmote leukocyte
recruitment
o IL-4 amplifies TH2 response
Summary of action of mast cell mediators in type I
hypersensitivity
Action
Vasodilation,
 vascular
permeability
Smooth
muscle
spasm
Cellular
infiltration
Mediators
Histamine
PAF
Leukotrienes C4, D4, E4
Neutral proteases that activate complement &
kinins
Prostaglandin D2
Leukotrienes C4, D4, E4
Histamine
Prostaglandins
PAF
Cytokines (chemokines, TNF)
Leukotriene B4
Eosinophil & neutrophil chemotactic factors
- eosinophils
o recruited in late phase rxn
o survival favored by IL-3, IL-5, and GM-CSF
o IL-5 = most potent eosinophil-activating
cytokine
o secrete major basic protein and eosinophil
cationic protein (toxic to epithelial cells)
- recruited cells amplify & sustain inflammatory
response w/o additional exposure to antigen
- susceptibility to type I hypersensitivity rxns is
genetically determined
o atopy = predisposition to develop localized
immediate hypersensitivity rxn to a variety of
inhaled/ingested antigens
o atopic pts have higher serum IgE and more IL-4
producing TH2 cells
Antibody-mediated (Type II) hypersensitivity
- caused by Abs that react w/ antigens present on cell
surfaces or in ECM
- rxn may result from binding of Abs to normal or
altered cell surface antigens
- antibody-mediated cell destruction & phagocytosis
o transfusion rxns
o hemolytic dz of the newborn (erythroblastosis
fetalis)
o autoimmune hemolytic anemia
o agranulocytosis
o thrombocytopenia
o drug rxns
- antibody-mediated inflammation:
o glomerulonephritis
o vascular rejection in organ grafts
- some Abs directed against cell surface receptors
impair function w/out causing cell injury or
inflammation (ex. myasthenia gravis)
- Abs may also cause stimulation of cell function (ex.
Graves dz)
Immune Complex-mediated (Type III)
hypersensitivity
- antigen-antibody complexes produce tissue damage
by eliciting inflammation at sites of deposition
- systemic immune complex dz
o acute serum sickness = prototype
o 3 phases: formation of complex in circulation
deposition of immune complex in various
tissues, inflammatory rxn at sites of immune
complex deposition
o complexes of medium size, formed in slight
antigen excess, are most pathogenic
o organs where blood is filtered at high pressure
to form other fluids are favored (urine, synovial
fluid)
o acute necrotizing vasculitis, smudgy
eosinophilic deposits, fibrinoid necrosis
o in kidney, complexes seen as granular lumpy
deposits of Ig & complement; on EM as electrondense deposits along glomerular BM
o SLE is a chronic form of serum sickness
- local immune complex dz (Arthus rxn)
o localized area of tissue necrosis from acute
immune complex vasculitis
o usually in skin
T cell-mediated (Type IV) hypersensitivity
- initiated by antigen-activated (sensitized) T
lymphocytes
- 2 types: reactions: delayed-type and cell-mediated
cytotoxicity
Reactions of CD4+ T cells: delayed-type hypersensitivity &
immune inflammation
- both TH1 and TH17 cells contribute to organ-specific
diseases in which inflammation is a prominent aspect
of the pathology
- TH1 rxn: dominated by macrophages
- TH17 rxn: greater neutrophil component
- CD4+ cells recognize peptides displayed by dendritic
cells  secrete IL-2  stimulate prolif. of antigenresponsive T cells
- antigen-stimulated T cells further differentiate to TH1
or TH17 by cytokines produced by APCs
o if APC secretes IL-12 differentiates to TH1
o IL-1, 6, 23, TGF-β  TH17
- upon exposure to antigen, TH1 secrete IFN-γ 
activates macrophages:
o  ability to phagocytose & kill microbes
o express more class II MHC molecules
o secrete TNF, IL-1  promote inflammation
o produce more IL-12  amplify TH1 response
- activated TH17 secrete IL-17, IL-22, chemokines
o recruit neutrophils & monocytes to rxn 
promote inflammation
o produce IL-21  amplify TH17 response
- tuberculin rxn
o intracutaneous injection of purified protein
derivative (PPD, aka tuberculin)
o previously sensitized pt will have reddening +
induration after 8-12 hrs (peak at 24-72 hrs)
- morphology:
o accumulation of mononuclear cells (mainly
CD4+ & macrophages) around venules
o perivascular cuffing
- granulomatous inflammation
o occurs w/certain persistent or nondegradable
antigens (tubercle bacilli colonizing lungs)
o perivascular infiltrate dominated by
macrophages over 2-3 weeks
o activated macrophages  epitheloid cells,
surrounded by collar of lymphocytes
(granuloma)
o assoc. w/ strong T-cell activation w/ cytokine
production
- contact dermatitis
o tissue injury resulting from DTH rxns
o may be from contact with urushiol (antigen in
poison ivy or oak)
Reactions of CD8+ T cells: cell-mediated cytotoxicity
- CD8+ CTLs kill antigen-bearing target cells
- tissue destruction by CTLs an important component of
dz (type 1 DM)
- CTLs against cell surface histocompatibility antigens
cause graft rejection
- play important role in viral inf.
- tumor-assoc. antigens killed by CTLs
- T cell-mediated killing of targets
o preformed mediators in lysosome-like granules
of CTLs
o CTLs that recognize target cells secrete a
complex consisting of perforin, granzymes, &
serglycin, which enters target cells by
endocytosis
o in target cell cytoplasm, perforin allows release
of granzymes from complex
o granzyme = proteases; cleave & activate
caspases  apoptosis of target cell
o activated CTLs express FASL which can also
trigger apoptosis of target cells
Autoimmune diseases
Central tolerance
- AIRE (autoimmune regulator)
o stimulates expression of peripheral tissue
restricted self-antigens in the thymus
o critical for deletion of immature T cells specific
for self antigens
o mutations in AIRE are cause of autoimmune
polyendocrinopathy
- receptor editing
o when developing B cells in the marrow strongly
recognize self-antigens, antigen receptor gene
rearrangement machinery is reactivated to
express new antigen receptors
o if receptor editing doesn’t occur, undergoes
apoptosis
Peripheral tolerance
- anergy
o prolonged or irreversible functional
inactivation of lymphocytes
o induced by antigen encounter w/o costimulator
(B7-1 & B7-2)
o CTLA-4 & PD-1 are inhibitory receptors on T
cells (homologous to CD28); cause anergy
instead of activation
o mutation in CTLA-4 or PD-1 causes
autoimmune dzes
o polymorphisms in CTLA-4 assoc. w/ some
autoimmune endocrine dz in humans
o if B cells encounter self-antigen in peripheral
tissues (esp. in absence of specific helper T
cells)  unable to respond to antigenic
stimulation and may be excluded from
lymphoid follicles  death
- suppression by regulatory T cells
o regulatory T cells develop mainly in thymus
(from recognition of self-antigens)
o ex. = CD4+ cells constitutively express CD25, α
chain of IL-2 receptor, and txn factor Foxp3
 Foxp3 & IL-2 needed for development &
maintenance of CD4+ regulatory T cells
 mutation in Foxp3  IPEX (immune
dysregulation, polyendocrinopathy,
enteropathy, X-linked)
- deletion by activation-induced cell death
o if T cells recognize self-antigens, express proapoptotic member of Bcl family (Bim)  death
by mitochondrial pathway
o Fas-FasL system
 Fas is expressed by lymphocytes and
many other cells
 FasL is expressed by activated T cells
 Fas + FasL interaction  apoptosis of
activated T cell
 mutation in Fas causes autoimmune
lymphoproliferative syndrome
- immune-privileged sites = testis, eye, brain
Susceptibility genes
- PTPN-22
o encodes protein tyrosine phosphatase
o gene MC implicated in autoimmunity
o assoc. with RA, type 1 DM, other autoimmune
dzes
- NOD-2
o cytoplasmic sensory of microbes
o assoc. w/ Crohn dz
- IL-2 receptor (CD25) and IL-7 receptor α chains
o assoc. w/ MS and other autoimmune dzes
Role of infections
- many autoimmune dzes assoc. w/ infections
- inf. may upregulate expression of costimulators on
APCs
- molecular mimicry = some microbes may express
antigens w/ same AA sequence of self-antigens and
trigger activation of self-reactive lymphocytes
o ex. = rheumatic  dz caused by Abs against
streptococcal proteins cross-react w/
myocardial proteins  myocarditis
Features of autoimmune dz
- epitope spreading = inf. damage tissues  release of
self-antigens  expose epitopes of antigens that
normally hidden from immune system  continuing
activation of lymphocytes that recognize previously
hidden epitopes
- TH1 responses – assoc. w/ destructive macrophagerich inflammation and production of Abs that cause
tissue damage by activation of complement
- TH17 responses – underlie inflammatory lesions
dominated by neutrophils & monocytes
Systemic lupus erythematosus (SLE)
- acute or insidious onset w/ chronic, remitting &
relapsing, often febrile illness
- injury to skin, joints, kidney, and serosal membrane
- affects mainly women
- 2-3fold higher in blacks & Hispanics than whites
- typically arises in 20s-30s
Spectrum of autoantibodies in SLE
- hallmark of dz = production of autoantibodies
- types of antinuclear antibodies (ANA):
o DNA
o histones
o nonhistone proteins bound to RNA
o nucleolar antigens
- 4 patterns seen on nuclear fluorescence:
o homogeneous or diffuse nuclear staining = Ab
to chromatin, histones, dsDNA
o rim or peripheral staining = dsDNA
o speckled pattern = MC pattern; non-specific;
non-DNA nuclear parts (Sm antigen,
ribonucleoprotein, SS-A, SS-B)
o nucleolar pattern = antibodies to RNA (seen MC
in systemic sclerosis)
- immunofluorescence for ANAs are sensitive but not
specific for SLE
- Ab for dsDNA & Sm antigen = diagnostic of SLE
- other antibodies include:
o blood cells (RBC, platelet, WBC)
o anti-phospholipid Ab (40-50%)
- phospholipids are complexed w/ proteins (including
prothrombin annexin V, β2-glycoprotein I, protein S,
and protein C)
- Ab against phospholipid-β2-glycoprotein complex also
bind to cardiolipin antigen (used in syphilis serology)
so SLE pts may have false pos. syphilis test
- antibodies have anticoagulant effect, but also have
complications of hypercoagulable state
Etiology & pathogenesis of SLE
- fundamental defect = failure of mechanisms that
maintain self-tolerance
- genetic factors:
o HLA-DQ linked to anti-dsDNA, anti-Sm,
antiphospholipid Abs
o deficiencies of early complement components
may impair removal of circulating immune
complexes
- immunological factors:
o failure of self-tolerance in B cells
o CD4+ helper T cells specific for nucleosomal
antigens also escape tolerance
- environmental factors:
o exposure to UV light exacerbates dz
o UV irradiation may induce apoptosis in cells 
alter DNA  immunogenic
o sex hormones have influence on development of
SLE (frequency in reproductive years 10x
higher in women; exacerbation during normal
menses & pregnancy)
o drugs (hydralazine, procainamide, Dpenicillamine) can cause SLE-like response
Mechanisms of tissue injury
- most visceral lesions are caused by immune
complexes (type III hypersensitivity)
- LE bodies or hematoxylin bodies = nuclei of damaged
cells complexed w/ Abs
- LE cell = any phagocytic leukocyte that has engulfed
the denatured nucleus of an injured cell
Morphology: kidney
- lupus nephritis affects up to 50%
o due to complex deposition in glomeruli, tubular,
or peritubular capillary BM, or larger BVs
- 5 patterns or lupus nephritis:
o class I – minimal mesangial
o class II – mesangial proliferative
o class III – focal proliferative
o class IV – diffuse proliferative
o class V – membranous
- mesangial lupus GN (class I & II)
o seen in 10-25%
o mesangial cell proliferation & immune complex
deposition w/o involvement of glomerular
capillaries
o class I – no/slight  in mesangial matrix & #
mesangial cells
o class II – moderate  in mesangial matrix & #
mesangial cells
o granular mesangial deposits of Ig and
complement always present
- focal proliferative GN (class III)
o seen in 20-35% of pts
o <50% involvement of glomeruli
o crescent formation, fibrinoid necrosis,
proliferation of endothelial & mesangial cells
o infiltrating leukocytes & eosinophilic deposits
o hematuria & proteinuria
- diffuse proliferative GN (class IV)
o most severe form of lupus nephritis
o 35-60% of pts
o glomerular changes same as class III
o entire glomerulus frequently affected
o >50% involvement of glomeruli
o hematuria & proteinuria
o HTN, mild to severe renal insufficiency
- membranous GN (class V)
o diffuse thickening of capillary walls
o 10-15% of pts
o severe proteinuria or nephrotic syndrome
- deposits in membranous lupus nephritis =
subepithelial
- deposits in proliferative types = supendothelial
o subendothelial deposits create homogenous
thickening of capillary wall (“wire loop” lesion)
o sees in focal & diffuse proliferative
- changes in interstitium & tubules frequent
Morphology: skin and joints
- characteristic erythema affects facial butterfly (malar)
area (bridge of nose & cheeks) in 50% of pts
- similar rash may be seen in extremities & trunk
- exposure to sunlight incites or accentuates erythema
- deposition of Ig and complement along
dermoepidermal junction
- joint involvement typically nonerosive synovitis w/
little deformity
Morphology: CNS
- antibody against synaptic membrane
- acute vasculitis
Morphology: cardiovascular
- pericarditis & inflammation of mesothelial surfaces
- pericardial involvement in up to 50%
- nonbacterial verrucous endocarditis
o single or multiple 1-3mm warty deposits on any
 valve on either surface of the leaflets
- coronary artery disease
Morphology: spleen, lungs, other tissues
- splenomegaly, capsular thickening, follicular
hyperplasia
- pleuritis and pleural effusions are MC pulmonary
manifestations (affect 50% of pts)
- LE, or hematoxylin bodies in bone marrow or other
organs strongly indicative of SLE
Clinical features
- highly variable clinical presentation
- typical picture is young woman w/ some of following:
o butterfly rash over face
o fever
o pain but no deformity in 1+ peripheral joints
(feet, ankles, knees, hips, fingers, wrists, elbows,
shoulders)
o pleuritic chest pain
o photosensitivity
- ANAs found in 100% of pts
- renal involvement:
o hematuria
o red cell casts
o proteinuria
o nephrotic syndrome
- hematologic problems: anemia, thrombocytopenia, etc.
- mental aberrations: psychosis, convulsions
- prone to inf.
- with appropriate tx, flare-ups and remissions span
years or decades
- MC cause of death = renal failure & intercurrent inf.
Chronic discoid lupus erythematosus
- skin manifestations mimic SLE but systemic dz is rare
- skin plaques w/ varying edema, erythema, scaliness,
follicular plugging, skin atrophy
- face & scalp usually affected
- may develop into SLE after many years
- 35% have pos. ANA test
- anti-dsDNA rare
Subacute cutaneous lupus erythematosus
- intermediate form btwn SLE & chronic discoid lupus
- predominant skin involvement
- skin rash more widespread, superficial, and
nonscarring compared to chronic discoid lupus
- mild systemic symptoms of SLE
- anti -SS-A
- HLA-DR3 genotype
Drug-induced lupus erythematosus
- hydralazine, procainamide, isoniazid, D-penicillamine
are a few drugs that can cause SLE-like syndrome
- multiple organs are affected but renal and CNS
involvement is uncommon
- anti-dsDNA is rare
- very high frequency of anti-histone
- HLA-DR4 allele at greater risk of developing SLE after
hydralazine admin.
Sjögren syndrome
- chronic dz characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth
(xerostomia) from immune-mediated destruction of
lacrimal & salivary glands
- 1 form = sicca syndrome
- 2 form = MC; in assoc. w/ other diseases (MC = RA;
others include SLE, polymyositis, scleroderma,
vasculitis, thyroiditis)
Etiology & pathogenesis
- lymphocytic infiltration & fibrosis of lacrimal &
salivary glands
- infiltrate mainly CD4+, some B cells
- 75% have RF
- ANAs in 50-80%
- Anti-SS-A (Ro) & anti-SS-B (La) = considered serologic
markers of this dz
- some (weak) assoc. with HLA alleles
- aberrant T-cell and B-cell activation
- initiating trigger may be viral inf. of salivary glands
(EBV or HCV)
- HTLV-1 sometimes get symptoms of Sjögren dz
Morphology
- in addition to lacrimal & salivary glands, other
exocrine glands may also be targeted
- periductal & perivascular lymphocytic infiltration
- lymphoid follicles w/ germinal centers seen in salivary
glands
- ductal lining show hyperplasia  obstruction of ducts
- atrophy of acini, fibrosis, hyalinization
- later in course: atrophy and replacement of
parenchyma w/ fat
- may appear like lymphoma if lymphoid infiltrate is
severe (high risk for B cell lymphoma)
- lack of tears  drying of corneal epithelium 
inflammation, erosion, ulceration
- oral mucosa atrophy w/ fissuring & ulceration
Clinical
- MC in women 50-60
- keratoconjunctivitis  blurry vision, burning, itching,
thick secretions accumulate in conjunctival sac
- zerostomia  difficulty swallowing solid foods,  in
taste, cracks/fissures in mouth, dry buccal mucosa
- parotid gland enlargement in half of pts
- dry nasal mucosa and epistaxis
- recurrent bronchitis and pneumonitis
- extraglandular dz:
o synovitis
o diffuse pulmonary fibrosis
o peripheral neuropathy
- defects in tubular function:
o renal tubular acidosis
-
o uricosuria
o phosphaturia
o can cause tubulointerstitial nephritis
60% have accompanying autoimmune disorder (MC
RA)
Mikulicz syndrome = combination of lacrimal +
salivary gland enlargement due to any cause
Dx: biopsy of lip to examine minor salivary glands
lymph nodes often hyperplastic
emergence of dominant B cell clone = indicative of
development of marginal zone lymphoma
5% of develop lymphoma
Systemic sclerosis (scleroderma)
- chronic dz characterized by:
o chronic inflammation from autoimmunity
o widespread damage to small BVs
o progressive interstitial & perivascular fibrosis
in skin & multiple organs
- excessive fibrosis throughout the body:
o skin (MC), GI, kidney, , muscles, lungs
- some pts remain confined to skin for many years but
mostly progress to visceral
- death due to renal failure, cardiac failure, pulmonary
insufficiency, or intestinal malabsorption
- diffuse scleroderma = widespread skin involvement at
onset w/ rapid progression and early visceral
involvement
- limited scleroderma = skin involvement often confined
to fingers, forearms, and face; late visceral
involvement
o may also develop CREST syndrome (calcinosis,
Raynaud’s phenomenon, esophageal
dysmotility, sclerodactyly, telangiectasia)
Etiology & pathogenesis
- autoimmune responses, vascular damage, & collagen
deposition  tissue injury
- CD4+ T cells responding to an unknown antigen
accumulate in skin & release cytokines that activate
inflammatory cells & fibroblasts
- cytokines produced by these T cells (TGF-β and IL-13)
stimulate txn of genes that encode collagen and other
ECM proteins (fibronectin) in fibroblasts
- inappropriate activation of humoral immunity
- all pts have ANAs that react w/ variety of nuclear
antigens; 2 ANAs strongly assoc:
o anti-Scl 70 (DNA topoisomerase I) in 10-20% of
pts w/ diffuse systemic sclerosis
o anticentromere antibody in 20-30% of pts w/
CREST syndrome or limited cutaneous systemic
sclerosis
Vascular damage
- microvascular dz consistently present early in dz; may
be initial lesion
- intimal proliferation in digital arteries
- capillary dilation w/ leaking & destruction
- nailfold capillary loops distorted early in dz; disappear
later
- repeated cycles of endothelial injury  platelet
aggregation  release of platelet & endothelial factors
(PDGF, TGF-β)  trigger perivascular fibrosis
Morphology: skin
- sclerotic atrophy of the skin begins in fingers & distal
regions of UE that extends proximally to involve upper
arms, shoulders, neck, face
- progressive fibrosis of dermis
- marked increase of compact collagen in dermis w/
thinning of epidermis
- hyaline thickening of walls of dermal arterioles &
capillaries
- in advanced stage, fingers become tapered, clawlike
appearance w/ limited ROM in joints
- face becomes drawn mask
- loss of blood supply  cutaneous ulcerations &
atrophic changes in terminal phalanges
- tips of fingers undergo autoamputation
Morphology: alimentary tract
- affected in 90%
- progressive atrophy & collagenous fibrous
replacement of muscularis may develop at any lvl of
gut (most severe in esophagus)
- lower 2/3 of esophagus develops rubber-hose
inflexibility  GERD, Barrett metaplasia, strictures
- musosa thinned and ulcerated
- malabsorption syndrome due to loss of villi
Morphology: MSK
- inflammation of synovium common in early stages 
fibrosis
- joint destruction not common
Morphology: kidneys
- renal problems in 2/3 of pts
- vascular lesions = most prominent
- interlobular arteries show intimal thickening
- concentric proliferation of intimal cells
- HTN seen in 30% (worse vascular alterations)
Morphology: lung & heart
- lungs involved in over 50%
- pulmonary HTN and interstitial fibrosis
- pericarditis w/ effusion and myocardial fibrosis occur
in 1/3 of pts
Clinical
- 3:1 female to male ratio
- peak incidence = 50-60 yrs
- striking cuteaneous changes (skin thickening)
- Raynaud’s in all pts (usually preceding feature)
- esophageal fibrosis  dysphagia
- pulmonary fibrosis respiratory difficulty  R-sided
 dysfunction
- myocardial fibrosis  arrhythmia or HF
- most ominous complication = malignant HTN  fatal
renal failure
- dz more severe in black women
- CREST syndrome
o pts have limited involvement of skin
o often confined to fingers, forearms, face, &
calcification of subQ tissues
o involvement of viscera occurs late or not at all
Mixed CT disease
- clinical features = mix of SLE, systemic sclerosis, and
polymyositis
- characterized serologically by high titers of Abs to
ribonucleoprotein particle-containing U1
ribonucleoprotein
- modest renal involvement
- good response to corticosteroids
- may evolve over time into classical SLE or systemic
sclerosis
Rejection of tissue transplants
T cell-mediated reactions
- aka cellular rejection
- destruction of graft cells by CD8+ CTLs and delayed
hypersensitivity rxns triggered by activated CD4+
helper cells
- direct pathway
o T cells of transplant recipient recognize
allogenic (donor) MHC molecules on surface of
APCs in the graft
o dendritic cells on donor organs are most
important APCs for initiating antigraft response
(express many class I and II MHC and
costimulatory molecules)
- indirect pathway
o recipient T lymphocytes recognize MHC
antigens of the graft donor after they are
presented by the recipient’s own APCs
o generates CD4+ T cells that enter the graft and
recognize graft antigens being displayed by host
APCs that have also entered the graft  delayed
hypersensitivity type of rxn
o can’t directly recognize or kill graft cells so
main way they reject is by T-cell production and
delayed hypersensitivity
- direct pathway is major pathway of acute cellular
rejection
- indirect pathway is more important in chronic
rejection
Antibody-mediated reactions
- aka humoral rejection
- hyperacute rejection occurs when preformed
antidonor antibodies are present in the circulation of
the recipient
Rejection of kidney grafts
- more kidneys have been transplanted than any other
organ
Hyperacute rejection
- occurs in mins or hours after transplantation
- becomes cyanotic, mottled, and flaccid
- may excrete a few drops of bloody urine
- Ig and complement are deposited in the vessel wall 
endothelial injury and thrombi
- thrombi  occlusion of capillaries  fibrinous
necrosis in arterial walls
- kidney cortex  necrosis
Acute rejection
- may occur within days or transplantation
- may occur after immunosuppression is terminated
- humoral rejection = vasculitis
- cellular rejection = interstitial mononuclear cell
infiltrate
Acute cellular rejection
- most common within initial months
- extensive interstitial mononuclear cell infiltration and
edema
- mild interstitial hemorrhage
- endothelitis – CD8+ cells injure vascular endothelial
cells
Acute humoral rejection (rejection vasculitis)
- mediated by antidonor antibodies
- mainly damage to BVs
- necrotizing vasculitis
- necrosis of renal parenchyma
- deposition of complement breakdown product C4d in
allografts
Chronic rejection
- emerging cause of graft failure
- present with progressive renal failure
- rise in serum creatinine in 4-6 mo.
- vascular changes – dense obliterative intimal fibrosis
 renal ischemia
- ischemia  glomerular loss, interstitial fibrosis,
tubular atrophy, shrinkage of renal parenchyma
- chronic transplant glomerulopathy
Methods of increasing graft survival
- HLA matching very beneficial in kidney transplant
- immunosuppressive therapy
o cyclosporine – mainstay of tx; blocks activation
of txn factor NFAT required for txn of cytokine
genes (IL-2)
o azathioprine – inhibits lymphocyte proliferation
o monoclonal anti-T-cell antibodies
- prevent host T cells from receiving costimulatory
signals from dendritic cells during initial phase of
sensitization by interrupting interaction btwn B7
molecules on dendritic cells of graft donor w/ CD28
receptors on host T cells (proteins that bind to B7
costimulators)
- immunosuppression may increase risk for developing
EBV-induced lymphomas, HPV-induced squamous cell
carcinomas, & Kaposi sarcoma
- mixed chimerism – recipient lives w/ injected donor
cells
Transplantation of hematopoietic cells
GVH disease
- immunologically competent cells or precursors are
transplanted into immunologically crippled recipients
& transferred cells recognize host’s alloantigens
- MC in bone marrow transplantation
- acute GVH dz
o occurs within days – wks after allogenic bone
marrow transplantation
o major affects in immune system & epithelial of
skin, liver, & intestines
o generalized rash  desquamation if severe
o destruction of small bile ducts  jaundice
o mucosal ulceration of gut  bloody diarrhea
o damage due to CD8+ T cells + cytokines
- chronic GVH dz
o may follow acute dz
o extensive cutaneous injury: destruction of skin
appendages and fibrosis of dermis
o chronic liver dz from cholestatic jaundice
o damage to GI tract  esophageal strictures
o involution of thymus and depletion of
lymphocytes in lymph nodes
o recurrent and life-threatening infections
- depletion of donor T cells before transfusion
o eliminates GVH dz
o graft failure incidence is higher
o EBV related B cell lymphoma risk
- immunodeficiency is a frequent complication of bone
marrow transplantation
o CMV inf. from previously silent inf.
o CMV pneumonitis can be fatal
X-linked agammaglobulinemia (Bruton’s
agammaglobulinemia)
- failure of B cell precursors to develop into mature B
cells
- mutation in bruton tyrosine kinase (Btk)
- X-linked
- becomes clinically apparent after 6 mo. of age when
maternal immunoglobulins depleted
- recurrent bacterial infections of respiratory tract (H.
influenza, S. pneumonia, S. aureus)
- B cells absent or very low; serum Ig very low
- germinal centers of lymph nodes, peyer’s patches,
appendix, tonsils underdeveloped
- plasma cells absent
- T-cell mediated immunity normal
Common variable immunodeficiency
- normal/near-normal B cell count
- hypogammaglonbulinemia
- recurrent sinopulomnary pyogenic infections
- recurrent herpesvirus infections
- female=male
- onset later (childhood/adolescence)
- B-cell areas of lymphoid hyperplastic
- high-frequency of autoimmune dz
- lymphoid malignancy risk
Isolated IgA deficiency
- low lvls of secretory and serum IgA
- familial or acquired (toxoplasmosis, measles, other
viral)
- most asymptomatic
- mucosal defenses weakened
- recurrent sinopulmonary infections and diarrhea
- respiratory tract allergy
- variety of autoimmune dz (SLE and RA)
Hyper-IgM syndrome
- make IgM antibodies but deficient in ability to make
IgG, A, E
- recurrent pyogenic infections, pneumonia (P. jiroveci)
- 70% X-linked; 30% AR
- mutation in CD40 or activation-induced deaminase
- autoimmune hemolytic anemia, thrombocytopenia,
neutropenia
DiGeorge syndrome (thymic hyperplasia)
- T-cell deficiency from failure of development of 3rd
and 4th pharyngeal pouches
- loss of T cell mediated immunity (lack of thymus)
- hypocalcemia (lack of parathyroids)
- congenital defects of heart and great vessels
- abnormal facies
- 22q11 deletion syndrome
- fungal and viral infections
SCID (severe combine immunodeficiency)
- defect in both humoral and cell-mediated immune
response
- infants present w/ thrush, diarrhea, FTT, morbiliform
rash (GVH)
- susceptible to recurrent severe infections
- 50-60% X linked; mutation in common γ-chain of
cytokine receptors
- most common cause of AR SCID = deficiency of
enzyme adenosine deaminase (ADA)
- thymus and other lymphoid tissues hypoplastic
- gene therapy successful but 20% developed acute Tcell leukemias
Wiskott-Aldrich syndrome
- X-linked recessive
- thrombocytopenia, exzema, marked vulnerability to
recurrent infection
- ends in early death
- response to protein antigens poor
- prone to NHL
- mutation in WASP
Complement deficiencies
- C2 = MC; increased SLE-like autoimmune dz
- C3 = needed for both classical & alternative pathway;
recurrent, serious pyogenic infections
- C5-9 = increased Neisseria infections
- C1 inhibitor = hereditary angioedema
o episodes of edema affecting skin and mucosal
surfaces (larynx and GI tract)
AIDS
- profound immunosuppression that leads to
opportunistic infections, secondary neoplasms, and
neurologic manifestations
- HIV-1 most commonly associated with AIDS in the US,
Europe, and central Africa
- HIV-2 causes similar dz in W. Africa and India
Structure of HIV
- p24 is most readily detected viral antigen
o target for antibodies used to dx HIV infection
- glycoproteins gp120 and gp41 stud the viral envelope
o critical for HIV infection of cells
- HIV-1 divided into 3 subgroups:
o M (major); most common worldwide
o O (outlier)
o N (neither M or O)
Life cycle of HIV
- infection of cells
o bind gp120 to CD4 molecules  conformational
change  new recognition site for coreceptors
(CCR5 and CXCR4)
o fusion of virus with host cell
o HIV genome enters cytoplasm
o requires HIV binding to coreceptors –
implications for resistance to infection
o infects memory and activated T cells, not
naïve cells bc of enzyme AP0BEC3G that
causes mutation in HIV genome
- integration of provirus into host genome
o reverse txn  synthesis of DS-complementary
DNA
o quiescent cells – cDNA remains in cytoplasm
o dividing cells – cDNA incorporated into host
genome
- activation of viral replication
- production and release of infectious virus
o after cell activation – cell lysis
Mechanism of T cell immunodeficiency in HIV
infection
- loss of CD4+ T cells is mainly bc of infection of cells
and direct cytopathic effects of replicating virus
- mechanisms that lead to loss of T cells:
o colonization of lymphoid tissues by HIV 
progressive destruction
o chronic activation of uninfected cells 
apoptosis (activation-induced death)
o loss of immature precursors
o fusion of infected and uninfected cells with
formation of syncytia (giant cells)  cell death
o apoptosis of uninfected cells by binding of
soluble gp120 to the CD4 molecule
- qualitative defects in T cells even in asymptomatic
person HIV-infected pts
- low level chronic of latent infection of T cells
Infection of non-T cells
- macrophages and dendritic cells
- important in pathogenesis of HIV infection
- macrophages are gatekeepers and potential
reservoirs of infection
- mucosal dendritic cells are infected by virus and
transport it to regional lymph nodes where virus is
transmitted to CD4+ cells
- AIDS pts cannot mount antibody responses to newly
encountered antigens
CNS involvement
- macrophages and microglia are predominant cell
types infected in brain
- neurologic deficits are caused by viral products and
soluble products from infected microglia
Natural history of HIV infection: primary infection
- dz begins with acute infection, which is only partly
controlled by the adaptive immune response,
advances to chronic progressive infection of
peripheral lymphoid tissues
- acute (early) infection characterized by:
o infection of memory CD4+ T cells (express
CCR5) in mucosal lymphoid tissues
o death of many infected cells
- mucosal infection is followed by dissemination of the
virus and development of host immune responses
- HIV specific CD8+ T cells are detected in the blood at
about same time viral titers begin to fall and are most
likely responsible for initial containment of HIV
infection
Acute retroviral syndrome
- self-limited acute illness
- non-specific symptoms
o sore throat
o myalgias
o fever
o weight loss
o fatigue
o flu-like picture after infection
o resolves in 2-4 weeks
- extent of viremia after acute infection is a useful
marker of HIV progression (measured as HIV-1 RNA
lvls)
- for clinical measurements, blood CD4+ counts are
most important
Chronic infection
- lymph nodes and spleen are sites of continuous HIV
replication and cell destruction
- phase of clinical latency
- asymptomatic or minor opportunistic infections
Progression to AIDS
- breakdown of host defenses
- dramatic increase in plasma virus
- severe, life threatening clinical dz
o serious opportunistic infections
o secondary neoplasms
o clinical neuro dz
- rapid progressors, long-term nonprogressors, elite
controllers (undetectable plasma virus)
Opportunistic infections
- majority of deaths in untreated AIDS pts die from
opportunistic infection (many from latent infection
reactivation)
- P. jiroveci causes pneumonia
- Candidiasis is MC fungal infection in AIDS pts
o esophageal, tracheal
-
CMV affects eye and GI tract
atypical mycobacteria (M. avium-intracellulare)
Cryptococcus can cause meningitis
T. gondii invades CNS
JC virus invades CNS; can cause progressive multifocal
leukoencephalopathy
- HSV causes mucocutaneous ulcerations involving
mouth ,esophagus, external genitalia, and perianal
region
- persistent diarrhea common
o usually caused by cryptosporidium
Tumors
- Kaposi sarcoma
o most common neoplasm in AIDS
o HHV8 virus (establishes latent infection)
o tumor is widespread (skin, mucous membranes,
GI tract, lymph nodes, and lungs)
- lymphomas
o 3 groups: systemic, primary CNS, and bodycavity based
o systemic lymphomas = involve lymph nodes
and visceral sites (80%)
o CNS = most common extranodal site affected
o most are aggressive B-cell tumors in advanced
stage
- increased incidence of carcinoma of cervix and anal
cancer
CNS disease
- meningoencephalitis
- aseptic meningitis
- vacuolar myelopathy
- peripheral neuropathies
- progressive encephalopathy (AIDS dementia
complex) – most common
Amyloidosis
- pathologic proteinaceous substance deposited in
extracellular space in various tissues and organs of
body in wide variety of clinical settings
- stains with Congo red
o regular light – pink or red color tissue deposits
o polarizing light – green birefringence
- continuous nonbranching fibrils
- cross-β-pleated sheet conformation
- most common forms of proteins:
o AL (amyloid light chain) from Ig light chains
made by plasma cells
 associated with plasma cell tumors
o AA (amyloid-associated) from unique non-Ig
protein made by liver
 increased in inflammatory states
 chronic inflammation
 secondary amyloidosis
o Aβ-amyloid produced from β amyloid precursor
protein
 found in Alzheimer disease
 comes from amyloid precursor protein
(APP)
- other proteins in amyloid deposits:
o TTR (transerytin) – familial polyneuropathies,
senile systemic
o β2-microglobulin – long term hemodialysis
o prion proteins
- amyloidosis results from abnormal folding of proteins
that become deposited as fibrils in extracellular
tissues and disrupt normal function
Classification of amyloidosis
- primary amyloidosis: immunocyte dyscrasias w/
amyloidosis
o most common form of amyloidosis
o plasma cell dyscrasia, multiple myeloma
o Bence-Jones protein
- reactive systemic amyloidosis
o AA protein
o secondary amyloidosis
o inflammatory condition
o most frequently associated condition = RA
o heroin abuse
o 2 most commonly associated tumors = RCC and
HL
- hemodialysis-associated amyloidosis
o β2-microglobulin
o renal dz
o often present with carpal tunnel syndrome
- heredofamilial amyloidosis
o most common is AR familial Mediterranean
fever (autoinflammatory)
 attacks of fever with inflammation of
serosal surfaces
 pyrin protein
 widespread amyloidosis
 AA proteins
- localized amyloidosis
o grossly detectable nodular masses or only
evident on microscopic
o oftein in lung, larynx, skin, bladder, tongue, and
periorbital
- endocrine amyloid
o medullary carcinoma of thyroid gland
o islet tumors of pancreas
o pheochromocytomas
o undifferentiated carcinomas of stomach
o islets of Langerhans in type 2 DM
- amyloid of aging
o senile systemic amyloidosis
o present with restrictive cardiomyopathy and
arrhythmia
o TTR molecule
o 4% of black population carriers of mutant allele
Morphology
- affected organs enlarged, firm, waxy appearance
- amyloidosis of kidney is MC and most serious form of
organ involvement
- splenic deposits limited to follicles; tapioca-like
granules (sago spleen)
- fusion of early splenic deposits  large maplike areas
of amyloidosis (lardaceous speen)
- heart major organ involved in senile systemic
- tumor-forming amyloid of tongue
- long-term hemodialysis  carpal tunnel syndrome
from median nerve compression