PATHOLOGY: DISEASES OF IMMUNITY (Part 1)

Lecturer: Michelle Anne Encinas, MD, DPSP

Immune system
Defense of the body
Defects in the immune system immunodeficiency states
infections, tumor growth, etc 2 Broad Ctegories:
INNATE
Hyperactive immune system
beforetransplant
rejection,
-present
infxn
autoimmunity, fatal diseases Evolved to recognize microbes and protect against infxn

Date: July 28, 2010

. Secrete interferon gamma and activate

macrophages

Innate ability to kill tumor cells, virally infected cells, normal cells
w/o previous sensitization, ADCC (Ab-dependent cell mediated
cytotoxicity)
Identified by their CD16 & CD56 cell surface molecules
Used as immunostain to recognize NK cells

Barriers:
Cells - lymphocytes,macrophages, plasma cells, NK cells
Cytokines/chemokines
Plasma chons
TLRs

Components of the immune system

Humoral immunity: mediated by Ab
Cellular immunity: mediated by lymphocytes
Cells of the immune system
T lymphocytes
B lymphocytes
Macrophages
Dendritic cells
Natural killer cells

ADAPTIVE
Adapt to microbes
Recognize microbial and nonmicrobial subs
2types:
Cellular
Humoral

Inhibitory receptor not engaged NK cells cannot attack

Plasma cells

T lymphocytes
Thymus- derived
60-70% of the lymphocytes in the circulating blood
Major lymphocyte type in the splenic periarteriolar sheaths and
LN interfollicular zones
Each T cell has a unique TCR that recognizes a specific peptide
fragment
Coreceptors for T cell stimulation: CD4 and CD8
CD4: Helper T cells
Expressed on 60% of mature T cells
Binds to class II MHC molecules during Ag recognition
Secrete cytokines
Plasma cells
A. Dendritic Cells
Round nucleus
2 subsets:
Ovoid cytoplasm
B. Langerhans Cells
TH1: secretes cytokines (IL-2, IFN)
that
help direct cellPeripheral
chromatin
"Clear zone"and
between
mediated immune responses, macrophages
NK nucleus
cells and wider lip of cytoplasm
INNATE versus ADAPTIVE IMMUNITY
TH2: secrete cytokines (IL-4, IL-5, IL-10) that antagonize TH1
Innate, Natural, Native
effects and promotes humoral immunity(IgE synthesis)
Acquired, Specific, Adaptive
immunity
CD8: Cytotoxic T cells
Present before infection
Expressed on 30% of T cells
After exposure to microbes
1st line of defense
Binds to class I MHC cells
Directly kills virus-infected or tumor cells
Recognize
antigens
or
Recognize microbes
Can also secrete cytokines
nonmicrobes
B lymphocytes
Bone marrow derived
10-20% of the circulating peripheral lymphocytes
Present in BM, peripheral lymphoid tissues, non lymphoid
organs
Localized to the lymphoid follicles (LN cortex) and splenic white
pulp
Final differentiation plasma cells secretes Ig (mediators
of humoral immunity)
Other cells of the Immune system:
Macrophages
Role in induction & effector phases of immune response
APC to T cells, DTH (activated by cytokines), Phagocytose
microbes opsonized by IgG or C3b
Dendritic cells
Non phagocytic cells seen in lymphoid tissues, interstitium of
nonlymphoid tissues
Interdigitating dendritic cells APC for primary immune
response to protein Ag present Ag to T cells (CD4+)
Langerhans cells- immature dendritic cells within epidermis
Follicular dendritic cells- germinal centers of lymphoid
follicles present Ag to B cells
NK cells
Large granular lymphocytes, function depends on balance of
inhibitory & activating receptors, also secrete cytokines

Transcribed by: Kristine Anne O. Cervales

Epithelial barriers, phagocytic

cells (PMNs, Macrophages),
NK cells, plasma proteins,
complement system

Lymphocytes & antibodies

Cell Mediated versus Humoral Immunity

CELL MEDIATED

HUMORAL

Intracellular microbes

Extracellular microbes & toxins

T-lymphocytes

B-lymphocytes & antibodies

Presence
of
TCR
gene
rearrangements marker for T
lineage cells

Rearranged Ig genes molecular marker of B lineage

cells

Not activated by soluble antigens;

require APCs to induce immunity;
membrane-bound antigens

Activated by protein
nonprotein antigens

CD8 (cytotoxic) bind Class I

MHC, kill other cells (cytokines)
CD4 (helper) bind Class II
MHC,
master
regulator
(cytokines)

B cells (cortex of LN & white

pulp of spleen), follicles
Plasma cells
IgM & IgD (cell surface) Ag
binding component

&

CYTOKINES MESSENGER MOLECULES OF IMMUNE SYSTEM

Short-acting soluble mediators
LMW polypeptides secreted by lymphocytes, effector cells and
APCs
Interleukins:
molecularly-defined
cytokines,
mediate
communication between leukocytes
Properties of Cytokines
Many cytokines are produced by different cell types (IL-1,
TNF can be produced by any cell)
Actions are pleiotropic (may act on many cell types & mediate
many effects) (IL-2)
Redundant: multiple cytokines induce same effects
Can act in amplifying cascades
Antagonistic:
regulate intensity and type of an immune
response
Mediate effects by binding to receptors on target cells
Induce effects in 3 ways:
- AUTOCRINE- act on same cell that produced them
- PARACRINE- affect other cells in vicinity
- ENDOCRINE- affect many cells systemically
General classes of cytokines
Mediators of innate immunity:
- IL-1, TNF, IL-6, IFN-1
- Protect against viral infections, initiate nonspecific
proinflammatory responses
- Macrophages: main source
Regulators of lymphocyte growth, activation and differentiation
- IL-2, IL-4, IL-5, TGF-a
Activators of inflammatory cells
- IFN-g, TNF, lymphotoxin, migration inhibitory factor
- T cells: main source
Chemokines
- Cytokines that act to recruit inflammatory cells to sites of
injury
- C-C: produced by T cells
- C-X-C: produced by activated macrophages and tissue
cells
Stimulators of hematopoiesis
- GM-CSF, G-CSF
- Lymphocytes and BM stromal cells: main source
Superantigens
Microbial proteins that bind to class II MHC molecules outside
the binding cleft
Polyclonal T-cell activators
When present, can activate a large percentage of T cells
widespread cytokine- mediated pathology
Staphylococcal enterotoxins, exfoliative toxins, TSS
Structure & Function of Histocompatibility Molecules
Cell surface molecules that bind peptide fragments of foreign
proteins for presentation to antigen-specific T cells
Located on chromosome 6 (MHC or HLA complex)
3 categories: chemical structure, function & tissue distribution
- MHC class I- cell surface glycoprotein
- MHC class II-cell surface glycoprotein
- MHC class III-components of the complement system

Generative lymphoid organs

Thymus
Bone marrow prodxn all blood cells
Peripheral lymphoid organs
Lymph nodes
Spleen
Mucosal and cutaneous lymphoid tissue

Transcribed by: Kristine Anne O. Cervales

MHC class I

MHC class II

Nucleated cells & platelets

APCs (macrophage, dendritic),

B cells

HLA-A, HLA-B, HLA-C loci

HLA-D (DP, DQ, DR

subregions)

Heterodimer (alpha & beta

microglobulin)

Heterodimer (alpha & beta)

Bind & display peptides(viral

Ag), present them to CD+8 T
cells

Present exogenous antigens

first internalized in endosomes
or lysosomes then present them
to CD4+ T cells

HLA & Disease association

Mechanism: unknown
Best known association Ankylosing spondylitis (HLA B27)
Inherited 90% of ankylosing spndylitis (hla b27)
Categories:
- Inflammatory diseases: arthropathies (HLA-B27)
- Inherited inborn errors of metabolism: 21 hydroxylase
deficiency (HLA-BW47) & hereditary hemochromatosis
(HLA-A)
- Autoimmune diseases: endocrinopathies (HLA-DR)
DISORDERS OF THE IMMUNE SYSTEM
HYPERSENSITIVITY REACTIONS
- Gives rise to immunologic injury
AUTOIMMUNE DISEASES
- Immune reactions against self
IMMUNOLOGIC DEFICIENCY SYNDROMES
- Genetically determined or acquired defect in immune
system component
AMYLOIDOSIS
- Poorly understood disorder with immunologic association
HYPERSENSITIVITY REACTIONS
Injurious immune reactions evoked by exogenous antigens
May be mediated by cellular or humoral immunity
Classified on the basis of immunologic mechanism that
mediates disease
IMMEDIATE HYPERSENSITIVITY (TYPE I)
- Release of vasoactive & spasmogenic substances &
proinflammatory cytokines Ige and mast cells
ANTIBODY-MEDIATED DSO. (TYPE II)
- Secreted Abs directly injure cells by promoting
phagocytosis or lysis & injury to tissues by promoting
inflammation; interference w/ cell fxn Igg and igm
IMMUNE COMPLEX-MEDIATED DSO. (TYPE III)
- Ag-Ab reactions induce inflammation directly or through
complement
CELL-MEDIATED IMMUNE DSO (TYPE IV)
- Sensitized T lymphocytes cause cellular & tissue injury
Type I hypersensitivity
Rapidly developing immune reaction occur within minutes after
Ag combine with Ab bound to mast cells in previously sensitized
Allergy; systemic or local reaction (depend on portal of entry)
"Immediate" mans seconds to minutes
2 phases: "Immediate allergic rxns" leading to anaphylaxis, shock, edema, dyspnea, death
- Immediate initial response (5-30 mins from exposure)Mastcells degranulation, vasodilation, vascular leakage, smooth muscle
vasodilation, edema, congestion, smooth muscle spasm
(broncho)-spasm
- Late phase (2-24 hrs later)- inflammatory infiltrate, tissue
destruction Eosinophils, PMNs, tcells
Ag is presented to CD4+ T cell, release of cytokines IL 4, 5 &
13, IgE production, eosinophil & mast cell activation on reexposure to allergen
Primary mediators- biogenic amines, enzymes, proteoglycans
Localized cutaneous
swelling
Secondary mediators- lipid mediators
& cytokines
Nasal and conjunctival discharge
Atopy- predisposition to develop
localized
immediate
HPSN rxn
Hay fever
to inhaled & ingested allergensBronchial asthma
Allergic gastroenteritis

Transcribed by: Kristine Anne O. Cervales

Mast cells and basophils FceRI- high affinity receptor; specific for IgE
Central to the development of type I hypersensitivity.
Mast cells:
- BM- derived, located near bv and nerves, subepithelial
sites
- Contain granules which serve as active mediators
- Triggered by crosslinking IgE, complement components,
cytokines, physical stimuli
Basophils:
- Not normally present in tissues
- Similar to mast cells
Primary mediators:
located within mast cell granules
released initiate early events in type I HPSN rxns
- Histamines, adenosine, chemotactic factors for neutrophils
and eosinophils
Secondary mediators:
- Leukotrienes:
o C4 and D4: most potent vasoactive and spasmogenic
agents
- Prostaglandin D2: most abundant mediator produced by the
cyclooxygenase pathway
- PAF
- Cytokines and chemokines (late phase reactions)
Clinical manifestations
Systemic: bee venom, drugs
- Itching, urticaria, erythema
- Dyspnea: bronchoconstriction, mucus hypersecretion,
laryngeal edema
- Vomiting abdominal cramps, diarrhea: GIT muscle spasm
- Anaphylactic shock: vasodilatation
Local: depends on route of exposure
- Skin and food allergy, hay fever, asthma
Type II hypersensitivity
Mediated by Abs directed toward Ag in cell surface or ECM
3 mechanisms
Complement- dependent reactions:
Direct lysis and opsonization: RBC most commonly
damaged
Transfusion reactions, erythroblastosis fetalis, autoimmune
hemolytic anemia, agranulocytosis & thrombocytopenia,
drug reactions, pemphigus vulgaris MEMORIZE!
Ab- dependent cell- mediated cytotoxicity (ADCC)
Kill via cells that bear receptors for the FC portion of IgG
Ag coated by Ab are lysed without phagocytosis or
complement fixation
Ab- mediated cellular dysfunction
- Ab directed against cell surface receptors impair or
dysregulate function w/o causing cell injury or inflammation
- Myasthenia gravis, Graves disease.

Autoimmune
hemolytic
anemia

RBC
membrane
protein (Rh & I
Ag)

Opsonization,
Phagocytosis

Hemolysis

Autoimmune
thrombocytop
enic purpura

Platelet
membrane
protein
gpIIb:IIIa,
integrin)

Opsonization,
Phagocytosis

Bleeding

Pemphigus
vulgaris

Epidermal
cadherin

Activated
proteases

Bullae

Vasculitis
from ANCA

PMN granule
proteins

PMN
degranulation

Vasculitis

Goodpasture
syndrome

Noncollagenoo
us protein in
BM

C & Fc
receptor med.
Inflamm.

Nephritis,
Lung hge.

Acute
rheumatic
fever

Streptococcal
cell wall Ag
(myocardial)

Inflammation &
macrophage
activation

Myocarditis
, arthritis

Myasthenia
gravis

Acetylcholine
receptor

Ab inhibits Ach
binding

Muscle
weakness

Graves
disease

TSH receptor

Ab stimulation
of TSH

Hyperfxn

Insulin
resistant DM

Insulin receptor

Ab inhibits
insulin binding

Hyperglyce
mia
ketoacidosi
s

Pernicious
anemia

Intrinsic factor

Neutralization
of IF

Anemia

Acute Gn

Bacterial
Ag
(treponema), parasite
Ag
(malaria,
schistosomes), tumor
Ag

Nephritis

Reactive
arthritis

Bacterial Ag (yersinia)

Acute arthritis

Arthus
reaction

Foreign proteins

Cutaneous vasculitis

Serum
sickness

Proteins
(foreign
serum), anti thymocyte
globulin

Arthritis,
vasculitis

nephritis,

Type IV hypersensitivity
Cell-mediated type of hypersensitivity initiated by Ag-activated T
lymphocytes
Mycobacterium TB, fungi, viruses, protozoa, parasites, contact
skin sensitivity to chemical agents, graft rejection, many
autoimmune diseases MEMORIZE!
Delayed type Mediated by CD4+ T cells
- Tuberculin reaction, intracellular pathogens, transplant
rejection, tumor immunity, contact dermatitis
- Cytokines involved: IL-12, IFN , IL-2, TNF & lymphotoxin,
chemokines
Direct cell cytotoxicity mediated by CD8 + T cells
- Graft rejection, virus infections
- 2 mechanisms of T cell mediated damage:
o Perforin-granzyme dependent killing (preformed
mediators)
o Fas-Fas ligand dependent killing- homologous to TNF,
induce apoptosis

Type III hypersensitivity

Ag-Ab complexes produce tissue damage by eliciting
inflammation at sites of deposition Blood vessel walls
Localized or generalized (Immune complex in circulation deposit
in a particular organ or many organs)
Systemic immune complex dse. At-Ab complex deposited in various tissues and organ
Local immune complex dse. Particular organ affected
- Arthus reaction- localized area of necrosis resulting from
acute immune complex vasculitis, usu. skin (venules)
- Develop over a few hours (peak 4-10), edema, hemorrhage
& ulceration
- Fibrinoid necrosis & thrombi lead to ischemic injury
Systemic immune complex disease
Phases:
- Formation of Ag-Ab complexes in the circulation (IgM, IgG,
IgA only)
- Deposition of the IC in various tissues
- Inflammatory reaction in various sites: symptomatic
o Vasculitis, GN, arthritis
Acute serum sickness: prototype disease
- Due to administration of foreign serum (horse ATS)
2 factors for tissue deposition:
- Size of IC: Ag excess, small- or intermediate- sized Ag
(not immediately cleared by phagocytes)
- Status of mononuclear phagocyte system: overload or
dysfunctional
SLE

DNA, nucleoproteins

Nephritis,
vasculitis

PAN

Hep B virus surface Ag

Vasculitis

Post-strep
GN

Streptococcal cell wall

Ag

Nephritis

Transcribed by: Kristine Anne O. Cervales

arthritis,

Direct antigen->cell contact

-granuloma formation
-contact dermatitis

Delayed-type hypersensitivity No antibodies involved

Tuberculin reaction:
Subcutaneous injection of tuberculin localized erythema
and induration in 24-72 hrs subsides
Cytokines involved:
- IL-12: produced by macrophages; induces DTH by
stimulating differentiation of TH1
- IFN-g:
most impt mediator of DTH; activator of
macrophages
- IL-2: causes proliferation of T cells at DTH sites
- TNF and lymphotoxin: exert effects on endothelial cells

Granulomatous inflammation
Granuloma:
a form of DTH due to persistent and/or
nondegradable Ag
T cell infiltrates are replaced by macrophages (2-3 wks)
become activated (epithelioid cells) fuse to form giant cells
surrounded by lymphocytes

Epitholoid cells

SUMMARY
Type I
Immediate

Anaphylaxis
Allergies
Bronchial
Asthma

IgE Ab
Release
of
vasoactive amines,
mast
cell
mediators,
recruitment
of
inflammatory cells

Vascular
dilation,
edema,
smooth
muscle
contraction,
mucus
production,
inflammation

Type II
Ab
mediated

Autoimmune
hemolytic
anemia
Goodpasture
syndrome

IgM, IgG binds Ag

on target cell lead
to
lysis
or
phagocytosis by
activated
complement or Fc
receptors;
WBC
recruitment

Cell
lysis,
inflammation

Type III
Immune
complex
mediated

SLE
Some GN
Serum
sickness
Arthus rxn

Ag-Ab
complex
deposits
Complement
activation
WBC recruitment
Enzyme or toxic
substance release

Necrotizing
vasculitis
(fibrinoid
necrosis),
inflammation

Type IV
Cellmediated

Contact
dermatitis
MS, TB
Type I DM
Transplant
rejection

Activated
T
lymphocytes
Cytokine release &
macrophage
activation
T-cell
mediated
cytotoxicity

Perivascular
cellular
infiltrates,
edema, cell
destruction,
granuloma
formation

T cell- mediated cytotoxicity

CD8 cells kill Ag- bearing target cells
2 mechanisms of CTL killing:
Perforin-granzyme- dependent killing:
- Perforin punches holes in the plasma membrane of cells
lysis of cells
- Granzymes activate target cell apoptosis
Fas-Fas ligand- dependent killing:
- Leads to apoptosis
Type 1 DM

Ag of pancreatic islet
Beta cells (insulin &
glutamic
acid
decarboxylase)

Insulitis, destruction of
beta cells, diabetes

Multiple
sclerosis

Protein Ag in CNS
myelin (myelin basic
protein & proteolipid
protein)

Demyelination in CNS w/
perivascular
inflammation, paralysis,
ocular lesions

Transcribed by: Kristine Anne O. Cervales

Rheumatoid
Arthritis

Unknown Ag in joint
synovium (type II
collagen?)

Chronic arthritis w/
inflammation, destruction
of articular cartilage &
bone

Peripheral
neuropathy
(Guillain
Barre ?)

Protein
Ag
of
peripheral nerve myelin

Neuritis, paralysis

TRANSPLANT REJECTION
Recipients immune response recognizes the graft as foreign
Transplant available for : skin, kidneys, heart, lungs, liver,
spleen, bone marrow, endocrine organs
Antigens responsible for rejection are HLA
Involve both cell-mediated & humoral immunity targeting the
graft vasculature (vasculitis)
T cell mediated reactions
- Destruction of graft cells by CD8+ CTLs, & DTH triggered
by CD4+ cells
- Recognition of Ag may be direct (dendritic cells in donor
organs, acute rejection) or indirect (recipient T cells
recognize Ag of graft donor presented by recipients APC,
chronic rejection)
Ab mediated reactions
- Hyperacute rejection- preformed anti-donor Abs in the
circulation of the recipient (prior transplant rejection,
mothers who have anti HLA Ab from exposure to fetus,
prior BT)
Morphology of Rejection Reactions (Renal transplant):
Hyperacute- w/in mins. or hours
- cyanotic kidney, mottling, flaccidity, bloody urine, Ag-Ab
rxns in the vascular endothelium, thrombi & complement
deposition, fibrinoid necrosis, cortical necrosis prompt
removal
Acute- w/in days, months or years later
- Acute Cellular Interstitial mononuclear infiltrate, inc.
serum creatinine, signs of renal failure, focal tubular
necrosis, endothelitis respond to immunosuppressive
therapy (cyclosporine)
- Acute Humoral necrotizing vasculitis w/ endothelial cell
necrosis, PMN infiltrate; Ig, fibrin & thrombi deposition,
extensive renal parenchyma necrosis, infarction or renal
cortical atrophy
Chronic- months to years
- progressive rise in serum creatinine (4-6 months), vascular
changes, interstitial fibrosis, tubular atrophy, loss of renal
parenchyma, duplication of basement membrane of
glomeruli, infiltrates of mononuclears, plasma cells 7
eosinophils
Transplant of Solid organs & Hematopoietic cells
Heart, liver, pancreas, lungs
No need for HLA typing, viability, availability & size of organ,
consider ABO blood type, absence of preformed Ab, body
habitus
3 problems in BM transplant: GVHD, transplant rejection &
immunodeficiency
GVHD- competent T cells transplanted to immunocompromised
recipient recognize the host cells as alloantigens
Immunodeficiency- from prior irradiation or drugs or from dse.;
danger of opportunistic infection notably CMV (pneumonitis)
Acute GVHD- days to weeks after BM transplant, affect immune
system, liver (jaundice), skin (rash & desquamation), intestines
(ulceration, diarrhea)
Chronic GVHD- extensive cutaneous injury, chronic liver dse.,
GI strictures, thymic involution, depletion of lymphocytes in LN,
infections
Methods of Increasing graft survival:
Minimize HLA disparity between donor & recipient (related
donor, match HLA class I & II alleles)
Immunosuppressive therapy

Cyclosporine- block activation of nuclear factor of activated

T cells required for cytokine gene transcription)
Azathioprine- inhibit leukocyte devt from BM precursors
Steroids- block inflammation
Rapamycin & mycophenolate mofetil inhibit lymphocyte
proliferation
Monoclonal anti-T cell antibodies- block T cell activation,
opsonize cells
Prone to infections, viral-induced tumors
Still under study :
- Induction of donor-specific tolerance in host T cells
- Antibodies w/c block CD40 ligand (inhibit humoral immune
response & CTL)
- Give donor cells to graft recipient to induce tolerance to
donor alloantigens (chimerism)
-

AUTOIMMUNE DISEASES
Immune reactions against self-antigens
Autoantibodies can be found in serum of older individuals
Three requirements: presence of autoimmune reaction, reaction
is not secondary to tissue damage, absence of another welldefined cause
Breakdown in self-tolerance (nonresponsiveness to ones
antigens)
Immunologic Tolerance- incapability to develop an immune
response;
Self-tolerance- ability to tolerate self-antigens
Central tolerance- deletion of self- reactive T and B
lymphocytes during their maturation in central lymphoid organs
Peripheral tolerance- autoreactive T cells that escape thymic
deletion can be removed or inactivated in the periphery by
different mechanisms

Failure of tolerance
Failure of activation-induced cell death
- Defects in the Fas-Fas ligand system persistence and
proliferation of autoreactive T cells
Breakdown of T-cell anergy
- Induction of anergic cells by infection or upregulation of
costimulator B7-1 (MS, RA)
Bypass of B-cell requirement for T-cell help
- Drug-induced, microbial-induced
Failure of T-cell- mediated suppression
Molecular mimicry
- Infectious agents share epitopes with self-Ag
- RHD:
Ab to M protein cross-react with cardiac
glycoproteins
Polyclonal lymphocyte activation
- Ag- nonspecific activation by microorganisms (endotoxin)
Release of sequestered Ag
- Self-Ag are reintroduced into the immune system
Exposure of cryptic self and epitope spreading
Genetic factors in autoimmunity
Familial clustering
- SLE, AIHA, AI thyroiditis
Link with HLA Ag
Induction of autoimmune diseases in transgenic rats
- HLA-B27 gene induction in rats caused ankylosing
spondylitis

Mechanisms in Peripheral Tolerance

Anergy- Irreversible functional inactivation of T cells in the
absence of costimulatory signals from normal parenchymal cells
Suppression by regulatory T cells- Regulatory T cells inhibit
lymphocyte activation & effector functions via cytokines (IL-10 &
TGF-)
Clonal deletion by activation-induced cell death- persistent
self-antigens cause activation of self-reactive T cells leading to
Fas ligand expression on these cells leading to apoptosis

Infection in autoimmunity
Microbes share cross-reacting epitopes with self-Ag
Microbial Ag and autoAg may form immunogenic units and
bypass T-cell tolerance
Some microbial products are nonspecific polyclonal mitogens
and may induce autoAb formation
Up-regulation of costimulatory molecules causing breakdown of
T-cell anergy
Induces epitope spreading

Mechanisms of Autoimmune Diseases

Bypass of immune tolerance through different pathways
involving susceptibility genes & environmental triggers
Involves interaction of immunologic, genetic and microbial
factors

Transcribed by: Kristine Anne O. Cervales

Transcribed by: Kristine Anne O. Cervales

PATHOLOGY: DISEASES OF IMMUNITY (Part 2)

Lecturer: Michelle Anne Encinas, MD, DPSP
Systemic lupus erythematosus
Autoimmune, multisystem, variable behavior
Principal organs: skin, kidneys, serosal membranes, joints and
heart
AutoAb: ANA, variable
1/2500 with a 1:9 M:F ratio (child-bearing age)
Etiology:
failure to maintain self-tolerance autoAb
production tissue damage or IC deposits
- Heritable defects in regulation of B cell proliferation
- Helper T cell hyperactivity (CD4+ T cells)

Date: July 28, 2010

Chronic Discoid Lupus Erythematosus- confined to skin

(dermal-epidermal junction), 5-10 % may eventually have
systemic manifestations
Drug-induced Lupus erythematosus
- Hydralazine, procainamide, isoniazid, D-penicillamine
- Multi-organ involvement (rarely renal/ CNS)
- Linkage to HLA DR4
- Remits after removal of inciting drug/agent

Antinuclear Ab
Ab to DNA: anti-dsDNA
Ab to histones: antihistone
Ab to nonhistone proteins bound to RNA: Anti-Sm, nuclear
RNP, SS-A (Ro), SS-B (La)
Ab to nucleolar Ag: Scl-70
Detected by IIF: pattern of nuclear fluorescence (diffuse, rim,
speckled, nucleolar)

SYSTEMIC LUPUS ERYTHEMATOSUS

Almost all are ANA (+): sensitive but not specific
Dx of SLE: anti-dsDNA and anti-Sm
Antiphospholipid Ab: seen in 40% of px
- May cause false (+) RPR
- Prolong PTT
Genetic factors: twin concordance, familial HLA clustering,
inherited deficiency of complement components
Nongenetic factors: drugs, sex hormones, UV light exposure
Immunologic factors: immunoregulatory disturbances
Acute necrotizing vasculitis
- Affects small arteries and arterioles
- May be seen in any tissue
- Necrosis, fibrosis, fibrinoid deposits within bv walls,
transmural WBC infiltrates
SYSTEMIC LUPUS ERYTHEMATOSUS SYSTEMIC EFFECTS
Kidneys- virtually all cases of SLE, principal mechanism is
immune complex deposition (COD 80%: renal failure)
o 5 classes: I (normal), II (mesangial lupus GN), III (focal
proliferative GN), IV (diffuse proliferative GN, most
common, most severe, worst prognosis, subendothelial), V
(membranous GN, subepithelial)
Skin- butterfly/malar rash (erythema over bridge of nose &
cheeks, worsen with sun exposure)
Joints- nonerosive nonspecific synovitis
CNS- neuropsychiatric manifestations, focal deficits, infarcts
Heart- Pericarditis/ serositis, Libman-Sacks endocarditis (small
warty vegetations,nonbacterial)
Spleen- moderate splenomegaly, follicular hyperplasia, fibrosis
Lungs- pleuritis, interstitial pneumonitis

Transcribed by: Kristine Anne O. Cervales

Rheumatoid arthritis
Systemic, chronic inflammatory disease
Joints are mainly affected
Nonsuppurative, proliferative synovitis destruction of
articular cartilage and bone arthritis
Other organs involved: skin, heart, bv, muscles, lungs
3-5 x more common in women
2nd-4th decades of life
Symmetric arthritis of small joints
Chronic synovitis pannus
- Synovial cell hyperplasia, IC infiltrates, bv proliferation,
osteoclast activity
- Fibrosis, calcification, ankylosis
Rheumatoid subcutaneous nodules
Vasculitic syndromes
Serositis, fibrosis, ocular changes (rare)
Etiology: genetic (strong association of HLA-DR4 and/or DR1,
RF seen in 80% of cases), environmental, infectious
Constitutional symptoms
Arthritis: aching and stiffness in the morning
Dx: x-ray findings, synovial fluid analysis, RF (80%)

Juvenile RA: no joint destruction, no RF, no nodules,

pauciarticular (large joints), associated with HLA-B27

SJOGREN SYNDROME
Characterized by dry eyes (keratoconjunctivitis sicca), dry
mouth (xerostomia), resulting from immune mediated lacrimal &
salivary gland destruction
40% isolated: sicca syndrome
60% associated w/ other autoimmune disorders (RA most
common)
90% females 35-45 years old
ANAs against RNP SS-A (Ro) (systemic), SS-B (La)
Association with infections : EBV, Hepatitis C, HTLV, HIV-1
Involve both cellular & humoral immune response
Miculicz syndrome - salivary gland & lacrimal gland enlargement
Diagnosis: lip biopsy
Other lesions: tubulointerstitial nephritis, RTA, LAD, B cell
lymphoma
SYSTEMIC SCLEROSIS (SCLERODERMA)
Excessive systemic fibrosis (most commonly in skin)
Affect the GIT, kidneys, heart, muscles & lungs M/M
Female : male (3:1) 50-60 year old
Symmetric edema, thickened hands, fingers (Raynaud
phenomenon- reversible vasospasm of arteries; paroxysmal
pallor & cyanosis of fingertips,
Classification:
- Diffuse scleroderma- widespread, visceral involvt, rapid
progression
- Localized scleroderma- (CREST syndrome), calcinosis,
Raynaud
phenomenon,
esophageal
dysmotility,
sclerodactyly, telangiectasia; minimal cutaneous involvt,
benign course
Etiology: unknown
Abnormal activation of immune system and microvascular injury
No intrinsic defect in collagen synthesis
Two ANAs seen:
o DNA topoisomerase I (anti-Scl 70)
Highly specific
70% of px with diffuse sclerosis
o Anticentromere Ab
- 90% of px with limited scleroderma
SCLERODERMA EFFECTS
Skin: diffuse, sclerotic atrophy, clawlike fingers, drawn mask
face, autoamputation
GIT: 90% of px, esophagus most severe, malabsorption sy
MS: no joint destruction
Lungs: >50% of px, PHPN, interstitial fibrosis
Kidneys: >60% of px, HPN in 30% of px
Heart: patchy myocardial fibrosis
INFLAMMATORY MYOPATHIES
Uncommon
Heterogeneous group of disorders characterized by immunemediated injury & inflammation of mainly the skeletal muscles
Immunologically mediated
3 distinct disorders
- Dermatomyositis: Ab-mediated
- Polymyositis: CD8- mediated
- Inclusion-body myositis: CD8- mediated
May occur alone or with other immune-mediated diseases
(systemic sclerosis)
Symmetric muscle weakness
Hx: lymphocytic infiltrates, degenerating/regenerating muscle
fibers
Anti Jo-1 Ab
MIXED CONNECTIVE TISSUE DISEASE
Coexistence of features of SLE, polymyositis, rheumatoid
arthritis, systemic sclerosis
Overlapping features
Serologically high titers of antibodies to RNP particle-containing
U1 RNP (anti-U1 RNP antibodies)
Paucity of renal disease
Good response to corticosteroids
Good long-term prognosis
85% with lung involvement (interstitial lung disease)
Transcribed by: Kristine Anne O. Cervales

POLYARTERITIS NODOSA / VASCULITIDES

Group of diseases characterized by necrotizing inflammation of
the walls of blood vessels which involves immunologic
mechanisms
General term is noninfectious necrotizing vasculitis
Involve
any type of vessel (arteries, arterioles, veins,
capillaries)
Encountered in many different settings

IMMUNOLOGIC DEFICIENCY SYNDROMES

Primary immunodeficiencies- hereditary, manifests in 6 months
Secondary
to 2 years of life (maternal Ab loss)
o X-linked Agammaglobulinemia of Bruton Immunodeficiencie-encoun
tered on individual with
o Common Variable Immunodeficiency
cancer, dM, and
malnutrition
o Isolated IgA Deficiency
o Hyper-IgM Syndrome
o DiGeorge Syndrome (Thymic Hypoplasia)
o Severe Combined Immunodeficiency Diseases
o Immunodeficiency with Thrombocytopenia & eczema
(Wiskott-Aldrich Syndrome)
o Genetic deficiencies of the Complement System
Acquired Immunodeficiency Syndrome (AIDS)- result from
altered immune function due to infection, malnutrition, aging,
immunosuppression, irradiation, chemotherapy, autoimmunity

X-linked Agammaglobulinemia of Bruton

Failure of pre-B cells to differentiate into B cells absence of
gamma globulin in blood
Basic defect is lack of mature B cells -mutation in B cell tyrosine
kinase gene (BTK) w/c has a role in signal transduction from
antigen receptor complex driving maturation
BTK maps to the X chr d/o is seen mostly in males
Virtually no serum Ig
Cell-mediated immune function is intact
LN & spleen lack germinal centers
Plasma cells are absent from all tissues
Present with recurrent bacterial infections after 6 months of age,
some viral, Giardia lamblia
- Bacterial pathogens that are cleared by Ab opsonization
(Haemophilus, Strep, Staph)
Most viral & fungal infections are handled (except enterovirus
echovirus & poliovirus)
Increased frequency of autoimmune connective tissue disease
Common Variable Immunodeficiency
Heterogeneous group of disorders, congenital & acquired,
sporadic & familial
Hypogammaglobulinemia affecting all immunoglobulin classes
(occasionally only IgG)
Impaired Ab response to infection or vaccine
Increased number of infection
Sexes are equally affected, 2nd-3rd decade of life
Pathogenesis, unclear; Intrinsic B cell defect, defective B cell
maturation as a result of T cell defect, complement genes in
HLA
Normal numbers of mature B cells
Absent plasma cells
Symptoms similar to agammaglobulinemia
Prone to autoimmune diseases & lymphoid malignancies
Isolated IgA Deficiency
Most common primary immunodeficiency disease
Virtual absence of serum & secretory IgA, occasionally IgG2 &
IgG4
Familial or acquired
Recurrent sinopulmonary & gastrointestinal tract infection
Prone to allergies & autoimmune diseases
Basic defect- failure in terminal differentiation of IgA positive B
cells to plasma cells
40% of cases have antibodies directed against IgA
Hyper-IgM Syndrome
Characterized by production of IgM but failure to produce IgG,
IgA and IgE antibodies
Failure of T cells to cause B cell switching to form
immunoglobulins (dependent on CD40L interaction)
In 70%, mutation of CD40L gene encoded on the X
chromosome (Xq26), X-linked
Recurrent bacterial infections
Susceptible to Pneumocystis carinii infection (T-cell
/macrophage interactions involve CD4-CD40L ligations)
DiGeorge Syndrome (Thymic Hypoplasia)
Multiorgan congenital disorder
Failure of development of 3rd & 4th pharyngeal pouches before
the 8th week of gestation
o Thymic aplasia/hypoplasia T cell deficiency
o Parathyroid hypoplasia hypocalcemic tetany
o Congenital heart & great vessel defects
o Dysmorphic facies
Deletion of a gene mapping to 22q11 (90% of cases)
Susceptible to viral, fungal, protozoal, intracellular bacterial
infections
Normal B cells and Ig
Treatment includes fetal thymus or thymic epithelium implants
Survival beyond 5th year of life T cell function can normalize
even with aplasia
Severe Combined Immunodeficiency Diseases
Defects in T & B cell function
Transcribed by: Kristine Anne O. Cervales

Autosomal or X-linked (50-60%)disorder

o X-linked- Mutation in common chain subunit of cytokine
receptors, affect lymphoid progenitor cytokines (IL-7)severe T cell defect
o AR- deficiency of enzyme adenosine deaminase
(accumulation of lymphocyte-toxic metabolites)
T cell defects lead to secondary B cell defects
Characterized by lymphopenia
Severe recurrent infections by pathogens
Atrophic lymphoid tissues, thymic hypoplasia
Tx- Bone marrow transplant
1st human dse for which gene therapy was successful

Immunodeficiency with Thrombocytopenia & eczema (WiskottAldrich Syndrome)

X-linked recessive disease
Thrombocytopenia, eczema, recurrent infections (esp to
encapsulated pyogenic bacteria)
Predilection for lymphoma
Morphologically normal thymus but there is progressive
peripheral T cell depletion defect in cellular immunity
Ab responses are variable (poor to polysaccharide antigens)
Defect maps to Xp11.23 (WASP gene)- protein product links cell
surface receptors & intracellular cytoskeleton
Tx- Bone marrow transplant
Genetic deficiencies of the Complement System
C2 deficiency is the most common - Not associated with serious
infections (alternative pathway is unaffected)
C3 deficiency affects both pathways susceptible to bacterial
infections
C1q, C2 & C4 inherited deficiencies- impaired immune complex
clearance (immune complex deposition)
Absent C1 esterase inhibitor- hereditary angioedema,
uncontrolled generation of vasoactive kinins
Defects in C5-8 result in recurrent neisserial infections (
intracellular, MAC complex-cellular lysis)
Secondary immunodeficiencies
Patients with malnutrition, infection, cancer, renal diseases,
sarcoidosis
Patients receiving CTX, RTX, IS drugs
Caused by loss of Ig, inadequate Ig synthesis, lymphocyte
depletion
More common than d/o of the primary ID
AIDS: most widespread and important secondary ID
AIDS
Infectious secondary form of immunodeficiency caused by HIV-1
(retrovirus)
Characterized by profound suppression of T cell mediated
immunity opportunistic infections, secondary neoplasms,
neurologic disease
HIV transmission: sexual contact, parenteral inoculation, vertical
transmission (mother to fetus)
5 major risks in US- homosexual men/bisexual (traumatized
rectal mucosa),intravenous drug users (contaminated needles &
paraphernalia), blood component recipients, hemophiliacs
(factor VIII concentrate prior to 1985), high-risk heterosexual
contact, no risk factor identified in 6% of cases
Risk of seroconversion after accidental needle stick (0.3%)
Worldwide, most common transmission occurs in male to female
(vaginal intercourse)
Transmission is facilitated by STDs with genital ulcerations
Sexual transmission: virus is present in semen enters
mucosa directly or by uptake into mucosal dendritic cells
Vertical transmission: transplacental, intrapartum, ingestion of
contaminated breast milk
Etiologic agent- HIV1 human type C retrovirus (animal
lentivirus); HIV-2 West Africa
o Nontransforming cytopathic retrovirus, causing target T cell
destruction
o HIV-1 lipid envelop derived from infected host membrane is
studded with gp120 & gp41

o Viral core contains major capsid protein p24, nucleocapsid

protein, 2 copies of genomic RNA, viral enzymes: protease,
integrase, reverse transcriptase; gag, pol, env genes
(codes for viral proteins)
o Genes present (not seen in other retroviruses)- TAT, VPU,
VIF, NEF, REV
o TAT & REV play a role in transcription

Pathogenesis:
o CD4+ helper T cell depletion is the central pathogenic
pathway of AIDS
o CD4 is the high-affinity receptor for HIV-1:
- gp120
- major chemokine coreceptors CCR5, CXCR4
o After binding of gp120 to CD4 & chemokine receptor, gp41
undergoes conformational change allow internalization of
virus
o Genome undergoes reverse transcription & proviral DNA is
integrated into the host DNA genome
o Transcription, translation & viral propagation with T cell
activation complementary DNA
o In the absence of T cell activation, infection enters a latent
phase
o Infection
of
lymphoid
organs
where
monocytes/macrophages act a viral reservoirs (transfer
virus to T cell on antigen presentation)

T cell depletion ensues with cell loss due to intracellular viral

replication with subsequent cell lysis (1-2 billion CD4+ T cells
are lysed daily)
Other modes of T cell loss:
o Progressive destruction of architecture & cellular
composition of lymphoid organs
o Chronic activation of uninfected cells (responding to
infection) leading to activation-induced cell death
o Fusion of infected & uninfected cells via gp120
o Binding of soluble gp120 to noninfected CD4+ T cells
leading to apoptosis or CTL-mediated killing
Consequences of HIV infection:
o T cell depletion
o Qualitative defects in T cell function
o Selective loss of T cell memory
o Paradoxic polyclonal B cell activation, intrinsic B cell
defects

T cells in HIV infection

Loss of CD4 cells occurs by both increased destruction and
reduced production
Inversion of CD4:CD8 ratio (N: 2:1)
AIDS: ratio <0.5
Qualitative defects also occur seen in asymptomatic HIVinfected persons
- Reduced Ag-induced T cell proliferation
- Impaired TH1 cytokine production
- Abnormal intracellular signaling
Monocytes/macrophages in HIV infection
Infected macrophages are found in tissues (brain, lungs)
Serve as portals of transmission
Also serve as reservoirs and vehicles for transport to other parts
of the body
Major site of replication when CD4 cells are already depleted
Dendritic cells in HIV infection
Mucosal dendritic cells: capture the virus and transport it to
regional LNs
Follicular dendritic cells: in the germinal centers of LN,
reservoirs of HIV
B cells and other lymphocytes in HIV infections
Hypergammaglobulinemia and circulating IC because of
polyclonal B cell activation
Despite presence of activated B cells, no Ab response mounted
Impaired humoral immunity susceptible to encapsulated
bacteria
CNS is a major target for HIV infection
Occurs predominantly by the infected monocytes/macrophages
in circulation
These infected cells activate or release toxic cytokines directly
or recruit other neuron-damaging inflammatory cells.
Tissue changes are nonspecific/nondxic except for CNS
Natural history:
o Infection has 3 phases:
- Early acute phase
- Middle chronic phase
- Crisis phase

Acute phase
Initial response of an immunocompetent adult to HIV
Self-limited; 3-6 wks after infection
Transient viremia, widespread seeding of lymphoid tissue
CD4+ T cell decrease
Seroconversion within 3-17 wks of exposure
o Virus-specific CD8 cells
o CD4 cells return to near normal numbers
o Virus replication within macrophages and CD4 cells
Chronic phase
Continued HIV replication in lymphoid tissues (years)
Slight decrease in CD4 cells (intact immunity)
Transcribed by: Kristine Anne O. Cervales

Asymptomatic, LAD, minor opportunistic infections (fungal,

herpes)

Crisis phase
Breakdown of host defenses
Increased viremia
Clinical disease: prolonged fever, wt loss, diarrhea
CD4 cell count: <500 cells/ul
AIDS-defining conditions:
serious opportunistic infections,
secondary neoplasms, neurologic manifestations
Full-blown AIDS: CD4 cell count </= 200/ul (CDC guidelines)
In absence of tx, HIV AIDS after 7-10 yrs in chronic phase
except:
o Rapid progressors: chronic phase last 2-3 yrs only
o Nonprogressors: asx for >/= 10 yrs

CDC classification according to CD4 cell count

>500 cells/ul: asymptomatic
200 500 cells/ul: early symptoms
<200 cells/ul: severe immunosuppression
CD4 cell count: status of px disease at time of measurement
Viral load: provides information regarding progression of the
disease
Clinical features of full-blown AIDS
o Opportunistic infections (pneumocystis pneumonia in 50%,
candidiasis,
CMV,
Mycobacteria,
cryptococcosis,
toxoplasmosis (CNS), cryptosporidiasis (GIT), HSV,
Papovavirus infection, Histoplasmosis)
o 80% of deaths in px
o Widespread Pyogenic bacterial infections
o Malignant neoplasms
- KS ( most common )- monoclonal spindle cell
neoplasm with prominent vascular component
associated with HHV-8
- Aggressive B cell NHL- EBV related, brain
involvement (2nd most common)
- SCCA uterine cervix- HPV related
o Clinical neurologic involvement (40-60%)
- Most common- progressive encephalopathy (AIDS
dementia complex)
- Acute aseptic meningitis
- Vacuolar myelopathy
- Peripheral neuropathy

o AA (amyloid associated)- non-immunoglobulin protein from

liver
o A amyloid- found in cerebral lesion of Alzheimer disease
Biochemical substances in amyloid:
o Transthyretin serum protein w/c transports thyroxine &
retinol
o 2-microglobulin- MHC class I component, normal serum
protein
o amyloid protein- core of cerebral plaques, and blood
vessel deposits in Alzheimer disease.
o Prion proteins- misfolded proteins, examples of local
amyloidosis
Minor components always present in amyloid:
o Serum amyloid P component, proteoglycans, highly
sulfated glycosaminoglycans
Amyloid deposition may be systemic or localized
Clinically classified as primary (immunocyte dyscrasia),
secondary (complication of underlying chronic inflammatory
dse.), hereditary or familial (distinct pattern of organ
involvement)
Primary amyloidosis- most common form, plasma cell dyscrasia,
systemic, AL form, MM, Bence Jones proteins
Reactive systemic amyloidosis- AA form, associated
inflammatory condition (connective tissue dso. -RA), or nonimmunocyte tumors (renal cell Ca and HD are the 2 most
common)

Clinicopathologic categories of amyloidosis

Reactive systemic
o AA protein
o Protracted cell injury due to chronic inflammation, nonimmunocyte-derived tumors (RCC, HD)
Heredofamilial
o Rare; limited to geographic areas
o Familial Mediterranean fever, familial amyloidotic
polyneuropathies
o AA protein
Localized
o Nodular deposits in single organs
o AL protein
Endocrine
o MCT, islet tumors, pheochromocytomas, undiff CA, DM
type II
Amyloid of aging
o Senile systemic amyloidosis (heart)
o Transthyretin (normal or mutant form)

Congo red stain

AMYLOIDOSIS
Systemic disease involving components of the immune system;
pathogenesis related to abnormal protein-folding which deposits
in tissues
Not a single disease but a group of diseases with a common
deposition of similar-appearing proteins
Amyloid- proteinaceous amorphous, eosinophilic, hyaline
extracellular substance deposited between cells in various
tissues & organs of the body in varied clinical settings, which
with progressive accumulation produces atrophy of adjacent
cells
Congo red stain- green birefringence of stained amyloid on
polarizing microscopy
Physical nature- non-branching fibrils, crossed -pleated sheet
conformation
- fibril proteins (95%), P component & glycoprotein (5%)
Chemical nature
15 biologically distinct forms, 3 most common:
o AL (amyloid light chain)- plasma cells

Transcribed by: Kristine Anne O. Cervales

Morphology
No consistent or distinctive patterns of deposition
Deposition always begins between cells accumulates
tissue destruction
Dx: congo red staining
o Light microscope: pink red deposits
o Polarized light: apple green birefringence
EM: amorphous nonoriented fibrils
Morphology is not consistent or distinctive but there are
generalizations:

o Secondary inflammation yields most severe systemic

involvements
o Commonly involve the kidney, liver, spleen, lymph nodes,
adrenals, thyroid
o Organs involved are enlarged, firm & waxy
o Kidney involvement is most common & most severe,
primarily in glomeruli
o Sago spleen deposition limited to follicles alone
o Lardaceous spleen- sinuses & red pulp of spleen
o Liver- sinuses, space of Disse, parenchyma, Kupffer cells
o Heart- major organ in senile systemic amyloidosis,
subendocardial & myocardial
o Other common organs: adrenals, thyroid, pituitary, GIT,
tongue, respiratory tract, nerves

Transcribed by: Kristine Anne O. Cervales