Immunopathology

Pathology Dr.Zainab Alhayali

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Immunological tolerance
Immunological tolerance is the phenomenon in which there is no
immune response to self antigens.
Self-tolerance: It is absence of immune response to an individual’s
own antigens.
Mechanisms of Self-Tolerance

 All immune and blood cells develop from multipotent hematopoietic stem cells
that originate in the bone marrow.
 Immature T cells undergo final maturation process in the Thymus that
"educates" them to distinguish between self and non-self antigens.
 Immature B cells undergo final maturation process in the Bone marrow.

Mature lymphocytes, the autoreactive T- cells and B- cells are deleted or

inactivated.

The mechanism by which this Self-Tolerance is achieved can be broadly classified

into two groups:
 Central tolerance: Immature lymphocytes that recognize self antigens in the
central (generative) lymphoid organs are killed by apoptosis. These organs are
thymus for T cells and the bone marrow for B cells.

 Peripheral tolerance: Mature lymphocytes that recognize self antigens in

peripheral tissues become functionally inactive (anergic), or are suppressed by
regulatory T lymphocytes, or die by apoptosis.
∞Anergy : irreversible inactivation ( rather than apoptosis) of lymphocytes .
AUTOIMMUNE DISEASES

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 Immunopathology
Pathology Dr.Zainab Alhayali
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Definition:

Immune reactions to self antigens due to the loss of self-tolerance

Mechanisms(causes)of Autoimmune Diseases
1. Failure of self tolerance
2. Environmental factors
3. Genetic susceptibility

 Failure of self tolerance

Failure of tolerance is due to several mechanisms:
1.Failure of activation induced cell death of the self-
reactive lymphocyte:

ANERGY

APOPTOSIS

SELF-
REACTIVE SUPRESSION BY T
REGULATORY CELL

2. Break down of T cell Anergy:

Anergy is broken when normal cell becomes expressing co-stimulatory molecules
required for T cell activation .
3. Modification in the structure of self antigen so became as a foreign antigen by T
cells.
e.g. autoimmune hemolytic anemia occurs after use of certain drug because the drug
induces change in the surface of RBCs that create an antigen which is recognized as a
foreign by T cells which subsequently stimulate B cells to produce autoantibodies
against RBCs leading to hemolysis.
4. Molecular Mimicry
Some infectious agents share the same epitope with self antigens, so immune response
against such microbes produces similar response to the self antigen.
e.g. polysaccharide coat of streptococci share the same epitope with cardiac
glycoprotein so after streptococcal throat infection, antibodies formed against bacteria
cross react with antigens in the heart wall leading to carditis (rheumatic heart disease)
and damage of endocardium, myocardium and pericardium.

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4
5. Release of sequestered antigens:
Any self antigen that is completely sequestered (hidden) from the immune system
during development is likely to be recognized as foreign antigen of it is subsequently
exposed to the immune system.

ENVIRONMENTAL FACTORS AND AUTOIMMUNITY

Role of infections in autoimmunity.
1) Molecular mimicry.
2) Upregulation of co-stimulatory molecules by infectious organisms.
3) Polyclonal B cell activation: caused by EBV and HIV resulting in production of
autoantibodies.
4) Alteration of tissue antigens: infections may alter tissue self antigens so that they
activate T cells and loose the property of self tolerance.
Autoimmune Diseases result in cell and tissue destruction by:
1. Type(VI) HSR: antigen-specific CD8 cytotoxic T cells
2. Type II and III HSR: autoantibodies (antibodies to self-proteins) and the accompanying
inflammatory process.
Examples of Autoimmune Diseases:
 Organ specific autoimmune disorders
 Type I diabetes mellitus
 Pernicious anemia
 Gravis disease
 Hypothyroidism
 Autoimmune hepatitis and primary biliary cirrhosis
 Multisystem autoimmune diseases
 Rheumatoid arthritis
 Systemic lupus erythematosus (SLE)
 Polyarteritis nodosa
 Auto immune hemolytic anemia
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE):
SLE is a systemic autoimmune disease caused by autoantibodies produced against
numerous self-antigens and the formation of immune complexes having following
characteristics:
1. Protean manifestation and variable behavior.
2. More commonly seen in the females around the age of 20-30’s
3. Remission and relapses.
4. Multisystemic involvement: Mainly affects skin, kidneys, joints, serous
membranes and heart.
5. Broad spectrum of autoantibodies: The auto-antibodies are formed against
DNA, histones, non histone proteins bound to RNA and nucleolar antigens.
These are collectively called as antinuclear antibodies (ANA).

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 Immunopathology
Pathology Dr.Zainab Alhayali
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Etiology

SLE is an autoimmune disease in which fundamental defect is failure of self-tolerance.

It leads to production of many autoantibodies that damages the tissue either directly or
indirectly by immune complex deposits.
Mechanisms of Tissue Injury
 Type III hypersensitivity: It occurs with deposition of immune complexes. It is
the most common cause of tissue injury and visceral lesions.
 Type II hypersensitivity: Autoantibodies against cell surface antigens specifi c
for RBCs, white cells, and platelets, opsonize these cells, promote their
phagocytosis and lysis, cytopenias
Pathogenesis of SLE

 Genetic Factors:
Evidence to support genetic predisposition are:
1. Familial association:
 Family members of SLE patients have an increased risk of SLE. About 20% of
unaffected first-degree relatives may show autoantibodies.
 High rate of concordance (>25%) in monozygotic twins when compared with
dizygotic twins (1%–3%).
2.HLA association: Risk is more with HLA-DR2 or HLA-DR3.
 Environmental Factors:
1. Ultraviolet (UV) radiation: Exposure to sunlight exacerbates the lesions of the
disease.
2. Mechanism: UV irradiation causes apoptosis of host cells, increases burden of
nuclear antigens and promote inflammation.
3. Cigarette smoking: It is associated with development of SLE.
4. Sex hormones: SLE is 10 times greater during the reproductive period (17
through 55 years) in women than in men. SLE shows exacerbation during normal
menses and pregnancy.
5. Drugs: Examples include hydralazine

 Immunological Abnormalities:
failure of self-tolerance with several immunological abnormalities of both innate and
adaptive immune system have been observed in SLE.

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4

The clinical criteria for the diagnosis of SLE

A person is considered to suffer from SLE if at least 4 of 11 clinical and
laboratory criteria are identified simultaneously or cumulatively at any
interval of observation.
1. Malar (‘‘butterfly’’) rash over the face
2. Discoid rash
3. Photosensitivity (rash as a result of sun exposure)
4. Oral ulcers
5. Arthritis (nondeforming polyarthritis)
6. Serositis (pleuritis and/or pericarditis)
7. Renal disorder (proteinuria of >0.5 g/day; cellular casts as signs of glomerulonephritis)
8. Neurologic disorder (seizures and/or psychosis)
9. Hematologic disorder (leukopenia, lymphopenia, thrombocytopenia, and hemolytic
anemia)
10.Immunologic disorder (antibodies to native DNA or Smith antigen [anti-Sm];
antiphospholipid antibodies)
11.Antinuclear antibody (in the absence of drug-induced lupus)

Any organ in the body can be affected & the

result is inflammation of the skin, joints,
kidneys, lung, heart, serosal surfaces….

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4
Tissue Transplantation
Grafts are divided into 4 types

The graft contain:

 Tissues of the organ (MHC)
 Some lymphocytes of the donor
 Some macrophage (APC) of the donor
Problems of Transplantation
 Graft rejection (Host versus graft)
 Graft versus host reaction (GVH)
Graft Rejection

1. It is a complex immunologic phenomenon as

responses of the host directed against MHC on the
donor graft.
2. The rejection happens because the MHC (HLA)
system of the donor is different from that of the
recipient so that both cell mediated immunity and
antibody response will be mounted against the
transplanted tissue.

3. The major types of hypersensitivity reactions involved

are types II, III and IV.
….Kidney is the most common transplanted organ

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4
MECHANISMS OF GRAFT REJECTION
1. CELLULAR REACTIONS : These are mainly responsible for graft rejection
and are mediated by T cells.

2. HUMORAL REACTIONS : These include: preformed circulating antibodies due

to pre-sensitisation of the recipient before transplantation e.g. by blood
transfusions and previous pregnancies.

Pathology, types of graft rejection

1-Hyperacute rejection:
 Pre-formed antidonor antibodies bind to graft endothelium
immediately after transplantation.
 This occurs due to previous sensitization by previous transplantation
and blood transfusion
 In the transplanted kidney the surgeon will notice, just after vascular
anastomosis, that the kidney will become cyanosed and secretes only
few drops of bloody urine.

 Microscopically, vasculitis with fibrinoid necrosis and thrombosis.

Hyper acute rejection of a kidney allograft showing endothelial vascular damage (by
preformed antibodies) with formation of fibrin-platelet thrombi in the glomerular
capillaries.
2-Acute rejection:
This occurs few days after transplantation
or after stoppage of the immunosuppressive
therapy.
 Acute cellular rejection: T cells destroy
graft parenchyma (and vessels) by
cytotoxicity and inflammatory
reactions.
 Acute humoral rejection: Antibodies
damage graft vasculature.
Microscopically
 Cellular rejection is manifested by
extensive interstitial mononuclear cell
infiltrate.
 Humoral rejection is manifested by acute necrotizing vasculitis leading to
narrowing of renal arterioles and infarction of renal cortex .

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4
This is a form of acute renal transplant rejection known as acute cellular
tubulointerstitial rejection because most of the inflammation is in the
interstitium. The glomerulus seen here is normal, but the tubules are
infiltrated by many lymphocytes at the upper right

Acute vascular rejection of the kidney with inflammatory cells in the

interstitium& in between the tubules.

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4

3-Chronic rejection:
Occurs after months-years after transplantation .
 This type is probably caused by T cell reaction and secretion of cytokines that
induce proliferation of vascular smooth muscle cells, associated with
parenchymal fibrosis.

 Microscopically: vasculitis with marked thickening of intima (intimal fibrosis)

leading to obliteration of vessel lumen and renal ischemia with fibrosis of
glomeruli, interstitial fibrosis and atrophy of tubules.

Chronic rejection of the kidney is dominated by interstitial fibrosis, tubular atrophy &
loss of renal parenchyma due to arteriolosclerosis of arteries.

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4
Methods of increasing graft survival:
1. The best results will be obtained from finding of HLA compatible
donor but unfortunately this is not available except from an identical
twin and 1:4 of brothers or sisters.
2. Immunosuppression like high doses of prednisolone or cytotoxic
therapy. Both cause non-specific immunosuppression and the patient
may suffer from opportunistic infections.

3. Now a days, antithymocytes antibodies are used.

Graft Versus Host Disease (GVHD)

Graft Versus Host Disease (GVHD)

Occurs most commonly during bone marrow transplantation and transplantation of
solid organs rich in lymphoid cells.

Before transplantation, we should destroy all the recipient marrow by total body irradiation
and cytotoxic drugs, and this will make the patient (recipient) immunodeficient.

When such recipients receive normal bone marrow cells from allogenic donors, the
immunocompetent T cells present in the donor marrow recognize the recipient’s HLA
antigen as foreign antigen and reacts against them.

Both CD4+ and CD8+T cells recognize and attack host tissues by generating DTH and cell
mediated cytotoxicity.

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 Immunopathology
Pathology Dr.Zainab Alhayali
Lec_4
The main cells involved in GVHD are CD8+ T-lymphocytes
The donor cells will attack the actively proliferating cells of the recipient resulting in
gastroenteritis (nausea & vomiting), skin rash, jaundice, etc…
GVHD is a lethal and can be minimized by:
 Proper HLA typing
 Donor T cells can be depleted before marrow transplantation

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