General Pathology for Lecture 9 Dr. Mukhallad A.

Ramadhan
College of Dentistry

DISEASES OF THE IMMUNE SYSTEM

• HYPERSENSITIVITY: IMMUNOLOGICALLY MEDIATED

TISSUE INJURY
Immune responses that normally are protective also are capable of causing tissue
injury. Injurious immune reactions are grouped under hypersensitivity, and the
resulting diseases are called hypersensitivity diseases.

• Causes of Hypersensitivity Reactions:

1. Autoimmunity: reactions against self antigens: Failure of self tolerance.
2. Reactions against microbes.
3. Reactions against environmental antigens.

• Classification of Hypersensitivity Reactions

Hypersensitivity reactions can be subdivided into four types based on the principal
immune mechanism responsible for injury.

1. Immediate (type I) hypersensitivity: often called allergy, the injury is caused

by TH2 cells, IgE antibodies, and mast cells and other leukocytes. Mast cells
release mediators that act on blood vessels and smooth muscle as well as
cytokines that recruit and activate inflammatory cells. This occur either as
local reaction (seasonal rhinitis, asthma) or systemic fatal reactions
(anaphylaxis). It occurs in two phases (1) the immediate response, which is
stimulated by mast cell granule contents and lipid mediators and is
characterized by vasodilation, vascular leakage, and smooth muscle spasm,
usually evident within 5 to 30 minutes after exposure to an allergen and
subsiding by 60 minutes; (2) a second, late-phase reaction stimulated mainly
by cytokines, which usually sets in 2 to 8 hours later, may last for several
days, and is characterized by inflammation as well as tissue destruction, such
as mucosal epithelial cell damage.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

Mechanism of type I hypersensitivity reaction

2. Antibody-mediated disorders (type II hypersensitivity: are caused by secreted

IgG and IgM antibodies that bind to fixed tissue or cell surface antigens e.g.;
autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in
which individuals produce antibodies to their own blood cells. Antibodies
injure cells by promoting their phagocytosis or lysis and injure tissues by
inducing inflammation. Antibodies also may interfere with cellular functions
and cause disease without cell or tissue injury e.g.; myasthenia gravis,
antibodies against acetylcholine receptors in the motor end plates of skeletal
muscles inhibit neuromuscular transmission, with resultant muscle weakness.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

3. Immune complex–mediated disorders (type III hypersensitivity): IgG and

IgM antibodies bind antigens, usually in the circulation, and form antigen-
antibody complexes that deposit in vascular beds and induce inflammation.
The leukocytes that are recruited (neutrophils and monocytes) produce tissue
damage by release of lysosomal enzymes and generation of toxic free radicals
e.g.; poststreptococcal glomerulonephritis.

4. T cell–mediated (type IV) hypersensitivity disorders: are caused mainly by T

cells: these are either
A. CD4+ T cells: including TH1 and TH17 which produces cytokines that
induce inflammation and activate neutrophils and macrophages, which are
responsible for tissue injury. Prolonged DTH reactions against persistent
microbes or other stimuli may result in development of granulomatous
inflammation.
B. CD8+ T Cell–Mediated Cytotoxicity: In this type of T cell–mediated
reaction, CD8+ CTLs kill antigen-expressing target cells. Tissue
destruction by CTLs may be an important component of some T cell –
mediated diseases, such as type 1 diabetes. CTLs directed against cell
surface histocompatibility antigens play an important role in graft
rejection.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

• AUTOIMMUNE DISEASES
Autoimmunity refers to immune reactions against self (“auto”) antigens.
Autoimmune diseases may be organ-specific, in which the immune responses are
directed against one particular organ or cell type and result in localized tissue
damage, or systemic, characterized by lesions in many organs. Generally
autoimmunity results from a failure of self-tolerance.

• IMMUNOLOGIC TOLERANCE
Self-tolerance refers to lack of immune responsiveness to one’s own tissue antigens,
there are two categories of immune tolerance:

A. Central Tolerance: The principal mechanism of central tolerance is the

antigen-induced deletion (death) of self-reactive T and B lymphocytes during
their maturation in central lymphoid organs.
B. Peripheral Tolerance: Self-reactive lymphocytes that escape negative
selection can inflict tissue injury so they are eliminated or muzzled in the
peripheral tissues.

1. I. Systemic Lupus Erythematosus:

SLE is an autoimmune disease involving multiple organs, characterized by a vast
array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury
is caused mainly by deposition of immune complexes and binding of antibodies to
various cells and tissues.

Injury to the skin, joints, kidney, and serosal membranes is prominent, but virtually
every organ in the body may be affected.

 Types of Antibodies in the SLE

 Anti-cytoplasmic antibodies.
 Anti-nuclear antibodies.
 Antibodies against cell surface antigens.

 MORPHOLOGY
A. Changes in the kidney: mainly glomerular inflammation due to
deposition of immune complexes in the glomerular components.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

(A) Focal proliferative glomerulonephritis (B) Diffuse proliferative glomerulonephritis

(C) wire-loop glomerular basement membrane

B. Skin: Characteristic erythema affects the face along the bridge of the
nose and cheeks (the butterfly rash) in approximately 50% of patients.

Butterfly rash

C. Joints: Joint involvement is typically a nonerosive synovitis with little

deformity, which contrasts with rheumatoid arthritis.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

D. Central Nervous System: noninflammatory occlusion of small vessels

by intimal proliferation, which may be due to endothelial damage
caused by autoantibodies or immune complexes.

E. Spleen. Splenomegaly, capsular thickening, and follicular hyperplasia

are common features. Central penicilliary arteries may show concentric
intimal and smooth muscle cell hyperplasia, producing so-called onion-
skin lesions.

Onion-skin lesion

1. II. Chronic Discoid Lupus Erythematosus:

Chronic discoid lupus erythematosus is a disease in which the skin
manifestations may mimic SLE, but systemic manifestations are rare.

2. Sjögren Syndrome:
This is a chronic disease characterized by dry eyes (keratoconjunctivitis sicca)
and dry mouth (xerostomia) resulting from immunologically mediated
destruction of the lacrimal and salivary glands.

 MORPHOLOGY
Lacrimal and salivary glands are the major targets of the disease, but other
exocrine glands, including those lining the respiratory and gastrointestinal
tracts and the vagina, also may be involved. The lacrimal and salivary
glands characteristically show dense lymphocytic infiltration consisting
mainly of activated CD4+ helper T cells and some B cells, including
plasma cells.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

• REJECTION OF TRANSPLANTS:
Acute rejection is mediated by T cells and antibodies that are activated by
alloantigens in the graft. It occurs within days or weeks after transplantation, and is
the principal cause of early graft failure. It also may appear suddenly months or even
years later, after immunosuppression is tapered or terminated

acute cellular rejection

tubulointerstitial pattern (sometimes called type I

vascular pattern shows inflammation of vessels (type II)

acute antibody-mediated (vascular or humoral) rejection.

This is manifested mainly by damage to glomeruli and small blood vessels

Chronic rejection: this is an indolent form of graft damage that occurs over months
or years, leading to progressive loss of graft function. Chronic rejection manifests as
interstitial fibrosis and gradual narrowing of graft blood vessels (graft
arteriosclerosis)

Graft-Versus-Host Disease

GVHD occurs when immunologically competent cells or their precursors are

transplanted into immunologically crippled recipients, and the transferred cells
recognize alloantigens in the host and attack host tissues. It is seen most commonly
in the setting of HSC transplantation but, rarely, may occur following transplantation
of solid organs rich in lymphoid cells (e.g., the liver).

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

Transplant Interstitial fibrosis and

Vascular obliteration due
glomerulopathy
to arteriosclerosis of the tubular atrophy, resulting
graft from arteriosclerosis of
arteries and arterioles in a
chronically rejecting
kidney allograft.

Immune Deficiencies:- this is either

I. Primary (or congenital) immunodeficiency disorders: these are genetically

determined and may include either innate or adaptive immunity.
These include:

1. Severe Combined Immunodeficiency:

Severe combined immunodeficiency (SCID) spans a constellation of
genetically distinct syndromes, all having in common impaired development
of mature T lymphocytes and/or B lymphocytes and defects in both humoral
and cell-mediated immunity.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

2. X-Linked Agammaglobulinemia:
X-linked agammaglobulinemia (XLA), or Bruton disease, is characterized by the
failure of pre–B cells to differentiate into mature B cells and, as the name implies,
a resultant absence of antibodies (gamma globulin) in the blood.
3. DiGeorge Syndrome (Thymic Hypoplasia):
DiGeorge syndrome is caused by a congenital defect in thymic development
resulting in deficient T-cell maturation.

4. Deficiencies Affecting the Complement System:

II. Secondary (or acquired) immunodeficiencies: this may be a complication

of:

1. Cancers.
2. Infections like HIV.
3. Malnutrition.
4. Side effects of immunosuppression.
5. Irradiation or chemotherapy for cancer and other diseases.

• ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

AIDS is a disease caused by the retrovirus human immunodeficiency virus (HIV)

and is characterized by profound immunosuppression tha leads to opportunistic
infections, secondary neoplasms, and neurologic manifestations.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

Pathogenesis of HIV Infection and AIDS:

While HIV can infect many tissues, the two major targets of HIV infection are the
immune system and the central nervous system.

Profound immune deficiency, primarily affecting cellmediated immunity, is the

hallmark of AIDS. This results chiefly from infection and subsequent loss of CD4+
T cells as well as impaired function of surviving helper T cells and other immune
cells.

Like the lymphoid system, the nervous system is a target of HIV infection.
Macrophages and microglia, cells in the CNS that belong to the macrophage lineage,
are the predominant cell types in the brain that are infected with HIV.

Clinical Features of AIDS

1. Opportunistic Infections: Opportunistic infections account for the majority

of deaths in untreated patients with AIDS. Common infections include:-

A. 30% of untreated HIV-infected individuals develop pneumonia caused by

the fungus Pneumocystis jiroveci.
B. Candidiasis.
C. Cytomegalovirus (CMV).
D. Mycobacterium aviumintracellulare.
2. Tumors: these include:-
A. Kaposi Sarcoma.
B. Lymphomas.
C. Carcinoma of the uterine cervix.

 AMYLOIDOSIS: Amyloidosis is a condition associated with a number of

disorders in which extracellular deposits of fibrillar proteins are responsible for
tissue damage and functional compromise, the three most common forms of
amyloid are the following:

• AL (amyloid light chain) amyloid: is made up of complete

immunoglobulin light chains, the amino-terminal fragments of light chains,
or both.

• AA (amyloid-associated): amyloid is derived by proteolysis from a larger

precursor in the blood called SAA (serum amyloid associated) protein,
which is synthesized in the liver.

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General Pathology for Lecture 9 Dr. Mukhallad A. Ramadhan
College of Dentistry

• β-amyloid protein (Aβ): this is derived by proteolysis from a much larger

transmembrane glycoprotein, called amyloid precursor protein.

THE END

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