AUTOIMMUNE DISEASES

-immune reactions against self-antigens

-autoantibodies can be found in apparently normal
individuals, particularly in older age groups

Requirements:
1. the presence of an immune reaction specific for
some self-antigen or self-tissue
2. evidence that such a reaction is not secondary to
tissue damage but is of primary pathogenic
significance
3. the absence of another well-defined cause of
disease

Examples:

Organ-specific diseases mediated by antibodies

Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Autoimmune atrophic gastritis of pernicious anemia
Myasthenia Gravis
Graves Disease
Goodpasture syndrome

Diseases Mediated by Antibodies – Systemic

SLE

Diseases Mediated by T-cells

DM Type I; multiple sclerosis
RA
Systemic scleroderma
Diseases Postulated to be Autoimmune :
Crohn’s Diseases
Ulcerative Colitis
Polyarteritis nodosa
Inflammatory myopathies

IMMUNOLOGIC TOLERANCE
-unresponsiveness to induced response from exposure
of lymphocytes to that antigen

Self-tolerance – lack of responsiveness to our own

antigens allowing us to live in harmony with our own
cells and tissues

- these cells have to be eliminated or

inactivated as soon as they recognize self-antigens, to
prevent them from causing harm.

CENTRAL Tolerance – immature self-reactive T and B

lymphocytes classes that recognize self-antigens during
their maturation in the central or generative lymphoid
organs are rendered harmless or killed

PERIPHERAL Tolerance- potentially autoreactive T and

B cells in peripheral tissues are rendered inactive or
silenced
a. anergy- activation of antigen-specific T-cells require
co-stimulators
-if the Ag is presented to T-cells without adequate
levels of co-stimulators, the cells become anergic
 b. suppression by regulatory T-cells
- A population of T-cells called regulatory T-cells
function to prevent immune reactions against self-
antigens
- they develop mainly in the thymus as a result of
recognition of self-antigens; also induced in
peripheral lymphoid tissues

b. Regulatory T-cells may play a role in the acceptance

of the fetus
c. Deletion by apoptosis
- T-cells that recognize self-antigens may receive
signals that promote their death by apoptosis

MECHANISMS OF AUTOIMMUNITY

-combination of the inheritance susceptibility genes

which may contribute to breakdown of self-tolerance
and environmental triggers such as infection, tissue
damage, which promotes the activation of self-reactive
lymphocytes.

1. defective tolerance or regulation

2. abnormal display of self-antigens
-increased expression and persistence of self-
antigens thst sre normally cleared
3. inflammation or an initial innate immune response
- innate immune response is strong stimulus for
subsequent activation of lymphocytes and generation of
adaptive immune responses
- microbes or cell injury may elicit local inflammatory
reactions resembling innate immune responses and
these may be critical inducers of the autoimmune
diseases

3. clinical and pathologic manifestations of

autoimmune diseases are determined by the
nature of the underlying immune response
-some of the diseases are caused by
autoantibodies
-most chronic inflammatory diaseases are caused
by abnormal or excessive TH1 and TH17
responses: ex. Psoriasis, multiple sclerosis,
inflammatory bowe diseases
- CD8+CTL’s contribute to the killing of cells
ex: islets of B-cells in type I DM
- RA- both anibodies and T-cell mediated
inflammation may be involved

4. Autoimmune diseases tend to be chronic, often

with relapses and remissions and the damage is
often progressive

- many intrinsic amplification mechanisms that allow

Ag specific lymphocytes to accomplish their task of
eradicating complex infection

- when directed against self-tissue, these same

amplification mechanisms exacerbate and prolong
the injury
- another reason for persistence and progression of
autoimmune diseases is the phenomenon of
epitope spreading, immune responses against
one’s self-antigen causes tissue damage, releasing
other antigens and resulting in activation of
lymphocytes In these newly-encountered epitopes

SPECIFIC DISEASES

Systemic Lupus Erythematosus (SLE)

-multiple organs
-vast array of autoantibodies
-particularly ANA- in which injury is cause mainly
by deposition of immune complexes and binding of
antibodies to various cells and tissues

-skin, joints, kidnes and mucosal membranes

-virtually every organ of the body
-female to male ratio: 9:1
- 2-3x in blacks and hispanics than white
-may manifest at any age, even in early childhood

Hallmark: Production of autoantibodies

-some antibodies recognize diverse nuclear and

cytoplasmic components of the cell that are
neither organ or species-specific and others are
directed against cell surface antigens of blood
cells
-failure of mechanisms that maintain self-tolerance
 ANA
a. Ab to DNA
b. Ab to histones
c. Ab to non-histone proteins bound to RNA
d. Ab to nucleolar antigens

CRITERIA FOR SLE (any 4 of the 11)

1. malar rash – fixed erythema, flat or raised over the

malar eminences, tending to spare the nasolabial
fold
2. discoid rash – erythematous raised patches with
adherent keratolytic scaling and follicular
plugging, atrophic scarring may occur in older
lesions
3. photosensitivity
4. oral and nasal ulceration – usually painless
5. arthritis – non-erosive, involves 2 or more
peripheral joints, tenderness, swelling and effusion
6. serositis- pleuritis-pain or rub or evidence of
pleural effusion; also pericarditis
7. renal disorders – persistent proteinuria, cellular
casts – RBC, Hgb, granular or tubular or mixed
8. neurologic diseases – seizures in the absence of
offending drugs or known metabolic derangements;
psychosis in the absence of the above; uremia,
ketoacidosis, or electrolyte imbalance
9. hematologic disorders – hemolytic anemia,
leukopenia, lymphophenia, thrombocytopenia
10. immunologic disorders – anti-DNA AB to native
DNA in abnormal titer
 11. ANA – abnormal titer

ENVIRONMENTAL FACTORS:
a. UV light – induce cell apoptosis and alters DNA –
becomes immunologic
b. Gender bias – sex hormones ; genes on the X-
chromosome
c. Drugs – hydralazine, procainamide and D-
penicillamine

MECHANISMS OF TISSUE INJURY

-immune complex type (Type III injury)

- DNA- anti-DNA complexes in glomeruli and small blood

vessels; lower levels of complement

- granular deposits of complement and immunoglobulins

in the glomerulus

-autoantibodies specific for RBC, WBC, and platelets

opsonize these cells and promote their phagocytosis
and lysis

- antiphospholipase Ab syndrome- venous and arterial

thrombosis, recurrent spontaneous miscarriages, focal
cerebral and ocular ischemia

-secondary antiphospholipid syndrome-

neuropsychiatric manifestations due to Ab that react
with neurons or receptors for various neurotransmitters
MORPHOLOGY:

a. blood vessels – acute necrotizing vasculitis –

fibrinoid deposits on vessel ealls, fibrous
thickening with luminal narrowing
b. kidney – up to 50% have clinically significant renal
involvement

-deposition of immune complexes that are

regularly present in the mesangium or along the
entire basement membrane and sometimes
throughout the glomerulus
1. Class 1 ( minimal mesangial lupus nephritis)
- uncommon, deposition of immune complex
2. Class 2 (mesangial proliferative lupus nephritis)
- mesangial proliferation, granular mesangial
deposits of immunoglobulin and complement
without involvement of glomerular capillaries
3. Class 3 (Focal Lupus Nephritis)
- involvment of fewer than 50% of glomeruli
4. Class 4 ( Diffuse Lupus Nephritis)
- most common and severe form
- half or more of glomeruli are affected
- segmental or global
- proliferation of endothelial, mesangial, and
epithelial tissues
-scarring of glomeruli
-thickening of the capillary walls
-hematuria, proteinuria, HPN and mild renal
insufficiency
5. Class 5 – ( Membranous Lupus Nephritis)
- diffuse thickening of capillary walls due to
immune complex deposition
-severe proteinuria and nephrotic syndrome

OTHER DISEASES

1. RA- chronic inflammatory disease

- joints, also extraarticular tissues such as
the skin, blood vessels and the heart
-autoimmune nature of the disease

2. Sjogren Syndrome
-chronic disease characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth
(xerostomia)
-immunologically mediated destruction of
lacrimal and salivary glands
- activated CD 4+ cells and some B-cells
-ANA detected in 50-80%
-75% rheumatoid factor positive (Ab reactive
with self IgG)
- pathogenesis remains obscure; aberrant T and
B cell activation
- may be triggered by viral infection of the
salivary glands, local cell death and release of
tissue self-antigens
-CD4+ T cells and B cells specific for these self
Ag may have escaped tolerance and are able to
react
 -common in women aged 50-60
-periductal and perivascular lymphocytic
infiltration
-infiltrate becomes extensive
-lymphoid follicles and germinal centers may be
seen
-hyperplasia of ductal lining epithelial cells-
obstruction of the ducts
-atropy
-lack of tears- drying of corneal epithelium,
which becomes inflammed, eroded and
ulcerated
- oral mucosa – atrophy, inflammatory fissuring
and ulceration
-dryness and crusting of the nose may lead to
ulceration and perforation of the nasal septum

SYSTEMIC SCLEROSIS (Scleroderma )

1. chronic inflammation as a result of

autoimmunity
2. widespread damage to small blood vessels
3. progressive interstitial and perivascular
fibrosis of the skin and multiple organs

-excessive fibrosis throughout the body

- skin most commonly affected
-also GI, kidney, heart, muscles and lung
_ remains confined in the skin for many years but
majority progress to visceral involvement and death
from renal failure, cardiac failure, pulmonary
insufficiency, intestinal malabsorption
 A. diffuse scleroderma – widespread skin involvement
at onset, rapid progression and early visceral
involvement
B. limited scleroderma- skin involvement often
confined to fingers, forearms and face, benighn,
visceral involvement occur later

PATHOGENESIS:

1. autoimmunity
2. vascular changes
3. collagen deposition

1. Autoimmunity
- CD4 T cells accumulate in the skin and release
cytokines that activate inflammatory cells and
fibroblasts
-TH2 cells have been isolated from the skin
-inappropriate activation of humoral immunity
-ANA’s provide diagnostic and prognostic
information

2. Vascular damage
- microvascular disease continuously present early
in the course of the disease and may be the initial
lesion.
- intimal proliferation of the digital arteries
- capillary dilatation with leaking and destruction
- repaeted cycles of endothelial injury, platelet
aggregation; release of platelet and endothelial
factors trigger perivascular fibrosis
 -exact cause of vascular injury is not known

3. Fibrosis – progressive fibrosis, culmination of

multiple abnormalities
- accumulation of alternatively activated
macrophages
-actios of fibrogenic cytokines released by
infiltrating leukocytes
- hyperresponsiveness of fibroblasts to these
cytokines
-scarring as a result of ischemic damage caused by
vascular lesions

Skin- diffuse, sclerotic atrophy

- finger and distal regions of the upper
extremities; extends proximally

CD4+ cells, swelling and degeneration of collagen

fibers; increased compact collagen in the dermis,
epidermal thinning, loss of rete pegs, atrophy of
the dermal appendages, and hyaline thickening of
the walls of dermal arterioles and capillaries

GIT- affected in 90% of patients

- progressive atrophy and collagenous fibrous
replacement of the muscularis may develop at any
level and is most severe in the esophagus
= rubber-hose like inflexibility, esophageal reflux,
barrett’smegtaplasia

-ulceration, malabsorption syndrome

 Musculoskeletal – infammation of the synovium,
associated with hyperplasia of the synovial soft
tissue, fibrosis
- joint destruction not common as compared to RA

Kidneys – 2/3 of patients

-vascular lesions – intimal thickening of
interlobular arteries as a result of deposition of
mucinous or firmly collagenous material
-not always associated with hypertension; no
specific glomerular changes

Lungs – 50%
- pulmonary hypertension and interstitial fibrosis

Heart – 1/3 of patients

- pericarditis with effusion, myocardial fibrosis,
thickening of intramyocardial arteries; clinical
impairment by myocardial involvement is rare
- virtually all patients have ANA

Inflammatory Myopathies
- uncommon, injury and inflammation of mainly skeletal
muscles probably immunoligally mediated
a. dermatomyositis
b. polymyositis
c. inclusion-body myositis
MIXED Connective Tissue Diseases
-clinical mixture of the features of SLE, systemic
sclerosis and polymyositis
- high titer of Ab to ribonucleoprotein particle
containing U1 ribonucleoprotein
-synovitis of the fingers, Raynaud’s phenomenon, and
mild myositis
- renal involvement is modest
-good respones to steroids
- pathogenesis not well undrestood
- IgG4 production in lesions is the hallmark of the
disease

REJECTION OF TISSUE TRANSPLANTS

-several immunologic reactions that underlie immune-
mediated inflammatory diseases

Rejection- immune system recognizes the graft as being

foreign and attacks it

T lymphocytes and antibodies produced against graft

antigens react against and destroy tissue grafts

RECOGNITION of graft alloantigens by T and B

lymphocytes

- the major antigenic differences between a donor and

recipient that results in rejection of transplants are
differences in HLA alleles
- Grafts exchanged between individuals of the same
species are called allografts

- Grafts from one species to another are called

xenografts

-Because HLA genes are highly polymorphic, there are

always some differences between individuals (except in
identical twins)

- Following transplantation, the recipient’s T cells

recognize donor antigens from the graft by direct and
indirect pathway of recognition

Direct Pathway
T cells of the transplant recipient recognize allogenic
{donor) MHC molecules on the surface of APC’s in the
graft
-dendritic cells carried in the donor organ are the most
important for initiating autograft response because they
not only express higher levels of Class I and II MHC
molecules and are also endored by costimulatory
molecules

-T cells of the host encounter the donor dendritic cells

within the grafted organs or when they migrate to
draining lymph nodes

= CD 8+ T cells recognize Class I MHC molecules and

differentiate into active CTL’s.
- CD 4 + helper cells recognize allogeneic class II
molecules znd proliferate and differentiatie into TH1
and probably TH 17 effector cells

INDIRECT PATHWAY OF RECOGNITION

-recipient T lymphocytes recognize MHC antigens of the

graft donor after they are presented by the recipient’s
own APC’s.

uptake and processing of MHC molecules from the graft

organ by the host’s APC’s

- the peptides derived from the donor tissue are

presented by the host’s own MHC molecules, like any
other foreign peptide
- similar to physiologic processing and presentation of
other foreign antigens

T-cell Mediated Reactions

1. acute cellular rejection- acute T-cell mediated

rejection
-seen within initial months after transplantation
-clinical and biochemical signs of organ failure
-inflammatory reactions in the graft triggered by
cytokines secreted by activated CD4+ T cells
- inflammation results in increased vascular
permeability and local accumulation of
mononuclear cells 9lymphos and macrophages,
 and graft injury is caused by activated
macrophages

-T cells also contribute to chronic rejection –

lymphocytes react against alloantigens in the
vessel wall, secrete cytokine that induce local
inflammation and may stimulate the proliferation of
vascular endothelium and smooth muscle cells.

ANTIBODY – MEDIATED REACTION

-antibodies produced against alloantigens in the
graft are also important mediators of rejection

a. Hyperacute rejection – preformed anti-donor

antibodies are present in the circulation of the
recipient
-in those who have previously rejected a
transplant
- multiparous woman who develops Ab against
maternal HLA antigens shed from the fetus may
have preformed antibodies that will react with
the grafts taken from their husbands or children

b. acute antibody mediated rejection

-antidonor antibodies produced after
transplantation
- targeted against graft vasculature

c. Chronic Antibody Mediated Rejection

- usually develops insidiously
 - without preceding acute rejection and primarily
affects the vascular components
-not well understood

REJECTION OF KIDNEY GRAFTS

1. Hyperacute Rejection – minutes to hours

-cyanotic, mottled, and may excrete a mere few
drops of bloody urine
- immunoglobulin and complement are deposited
in the vessel wall, causing endothelial injury and
fibrin-platelet thrombi
- rapid accumulation of neutrophils within
arterioles, glomerolus and peritubular capillaries
-glomeruli undergo thrombotic occlusion of
capillaries; fibrinoid necrosis of arterial walls
-cortex undergoes outright necrosis (infarction)
and the non-functional kidney has to be removed

2. Acute rejection – may occur within days or even

months and even years later if left untreated
-cellular and immune mechanisms may prevail

3. Acute cellular rejection (t-cell mediated

rejection or Type I)
-extensive interstitial inflammation with
infiltration of the tubules, Tubulous
- CD4+ and CD 8+ T lumphocytes
-endothelitis – inflammation of the vascular
walls
-swelling of endothelial cells
4. Acute Antibody mediated rejection
- damage to glomeruli and small blood vessels
-inflammation of glomeruli and peritubular
capillaries
-deposition of complement breakdown products
C4d
-small vessels with focal thrombosis

CHRONIC REJECTION

-largely controlled by immunosuppressive

therapy
-progressive renal failure, rise in CREA in a
period of 4-6 months
- dominated by vascular changes
a. initial thickening with inflammation
b. glomerulopathy, duplication of basement
membrane
c. peritubular capillaritis and and multi-layering
of peritubular capillary basement membrane