Diseases of Immune System

Part 2
By
Dr Muchindu N
Anatomical Pathology Registrar
Autoimmune Diseases
 Introduction
• Autoimmunity refers to immune reactions against self (“auto”)
antigens.

• Autoimmune diseases may be organ-specific or systemic.

• In systemic diseases, the lesions principally affect the connective

tissues and blood vessels of involved organs.

• Thus they are referred to as collagen vascular diseases or

connective tissue diseases

• Normal persons are unresponsive (tolerant) to their own (self)

antigens, and autoimmunity results from a failure of self-
tolerance.
 Immunologic Tolerance
• Immunologic tolerance is a state of
unresponsiveness to an antigen that is
induced by exposure of specific lymphocytes
to that antigen.

• Self-tolerance refers to lack of immune

responsiveness to one’s own tissue antigens.
Central Tolerance
• The antigen-induced deletion (death) of self-
reactive T lymphocytes and B lymphocytes
during their maturation in central (generative)
lymphoid organs (i.e., in the thymus for T cells
and in the bone marrow for B cells).
Peripheral Tolerance
• Mechanisms involved to silence potentially
autoreactive T cells and B cells in peripheral
tissues.

• These mechanisms include the following:

– Anergy
– Suppression by regulatory T cells
– Deletion by apoptosis
Anergy.
• This term refers to functional inactivation (rather than
death) of lymphocytes that is induced by encounter
with antigens.

• Activation of T cells requires two signals: recognition of

peptide antigen in association with MHC molecules on
APCs, and a set of second costimulatory signals
provided by the APCs.

• If the costimulatory signals are not delivered, the T cell

becomes anergic and cannot respond to the antigen.
Suppression by regulatory T cells.
• A population of T cells called regulatory T cells functions
to prevent immune reactions against self antigens.

• Regulatory T cells develop mainly in the thymus, but

they also may be induced in peripheral lymphoid tissues.

• Examples of regulatory T cells are CD4+ cells and express

high levels of CD25, the α chain of the IL-2 receptor, and
a transcription factor called FOXP3.

• Both IL-2 and FOXP3 are required for the development

and maintenance of functional CD4+ regulatory T cells.
Deletion by apoptosis.
• T cells that recognize self antigens may receive
signals that promote their death by apoptosis
by upregulating a pro-apoptotic member of
the Bcl-2 family called Bim, which triggers
apoptosis by the mitochondrial pathway

• Another mechanism of apoptosis involves the

death receptor Fas (a member of the TNF
receptor family)
 Mechanisms of Autoimmunity
• The breakdown of self-tolerance and
development of autoimmunity result from
the combined effects of susceptibility genes,
which influence lymphocyte tolerance, and
environmental factors, such as infections or
tissue injury, that alter the display of and
responses to self antigens
Genetic Factors in Autoimmunity

• There is abundant evidence that inherited genes play

a role in the development of autoimmune diseases.

• Autoimmune diseases have a tendency to run in

families, and there is a greater incidence of the same
disease in monozygotic than in dizygotic twins.

• Several autoimmune diseases are linked to the HLA

locus, especially class II alleles (HLA-DR, HLA-DQ).
Role of Infections, Tissue Injury, and Other
Environmental Factors

• Microbial infections with resultant tissue necrosis and

inflammation can stimulate expression of
costimulatory molecules on APCs in the tissue, thus
favoring a breakdown of T cell tolerance and
subsequent T cell activation.

• Viruses and other microbes may share cross-reacting

epitopes with self antigens, and as a result responses
induced by the microbe may extend to self tissues, a
phenomenon called molecular mimicry.
 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.

• The presentation of SLE is so variable that a

complex set of criteria for this disorder have
been proposed

• SLE predominantly affects women, with a

female-to-male ratio of 9 : 1 for the
reproductive age group of 17 to 55 years.
• The hallmark of SLE is the production of
autoantibodies.
• Some antibodies recognize nuclear and
cytoplasmic components, while others are
directed against cell surface antigens of blood
cells.
Anti-Nuclear Antibodies
ANAs can be grouped into four categories:
1. Antibodies to DNA,
2. Antibodies to histones,
3. Antibodies to nonhistone proteins bound to
RNA
4. Antibodies to nucleolar antigens.
Other Autoantibodies
• Some are directed against blood cells, such as
red cells, platelets, and lymphocytes.

Anti-phospholipid
• They are directed against epitopes of various
plasma proteins.
 Pathogenesis

• The fundamental defect in SLE is a failure of

the mechanisms that maintain self-tolerance.

• Genetic

• Environmental factors play a role.

Genetic Factors
• Familial association. Family members have an
increased risk for the development of SLE, and
up to 20% of unaffected first-degree relatives
have autoantibodies.

• HLA association. The odds ratio (relative risk)

for persons with HLA-DR2 or HLA-DR3 is 2 to
3, and if both haplotypes are present, the risk
is about 5.
• Other genes. Genetic deficiencies of classical
pathway complement proteins, especially C1q,
C2, or C4, are seen in about 10% of patients
with SLE.
Environmental Factors
• UV irradiation may induce apoptosis and also
may alter DNA and make it immunogenic,
perhaps by enhancing its recognition by TLRs.

• Drugs such as hydralazine, procainamide, and

D-penicillamine can induce an SLE-like disorder.
 Mechanisms of Tissue Injury

• Most of the systemic lesions are caused by

immune complexes (type III hypersensitivity).

• Autoantibodies of different specificities

contribute to the pathology and clinical
manifestations of SLE (type II hypersensitivity)
 Clinical Features

• SLE is a highly variable multisystem disease, and its diagnosis

relies on a constellation of clinical, serologic, and morphologic
findings.

• It may be acute or insidious in its onset.

• Often, the patient is a young woman with some or all of the

following features:
– A butterfly rash on the face
– Fever
– Pain without deformity in one or more joints;
– Pleuritic chest pain
– Photosensitivity
 Rheumatoid Arthritis

• Rheumatoid arthritis is an autoimmune

disease that affects primarily the joints but
also may involve extraarticular tissues such as
the skin, blood vessels, lungs, and heart.
 Sjögren Syndrome

• A chronic disease characterized by dry eyes

(keratoconjunctivitis sicca) and dry mouth
(xerostomia) resulting from immunologically
mediated destruction of the lacrimal and
salivary glands.

• Rheumatoid arthritis is the most common

associated disorder.
Clinical Features
• Keratoconjunctivitis produces blurred vision,
burning, and itching, and thick secretions that
accumulate in the conjunctival sac.

• Xerostomia results in difficulty in swallowing

solid foods, a decrease in taste, cracks and
fissures in the mouth, and dryness of the
buccal mucosa.
 Systemic Sclerosis (Scleroderma)

• An immunologic disorder characterized by excessive

fibrosis in multiple tissues, obliterative vascular
disease, and evidence of autoimmunity, mainly the
production of multiple autoantibodies.

• Cutaneous involvement is the usual presenting

manifestation and eventually appears in
approximately 95% of cases

• The visceral involvement of the gastrointestinal tract,

lungs, kidneys, heart, and skeletal muscles is
responsible for most of the morbidity and mortality.
 Pathogenesis

• The cause of systemic sclerosis is not known,

but the disease likely results from three
interrelated processes— autoimmune
responses, vascular damage, and collagen
deposition
 IgG4-Related Disease

• IgG4-related disease (IgG4-RD) is a newly

recognized constellation of fibro-inflammatory
disorders characterized by tissue infiltrates
rich in IgG4 antibody-producing plasma cells
and lymphocytes, particularly T cells,
associated with fibrosis and obliterative
phlebitis
Rejection of Transplants
 REJECTION OF TRANSPLANTS

• Rejection is a process in which T lymphocytes and

antibodies produced against graft antigens react
against and destroy the grafts

• The major antigenic differences between a donor

and that result in rejection of transplants are
differences in HLA alleles

• Because HLA genes are highly polymorphic, there

are always some differences between individuals
(except, of course, identical twins).
Immunodeficiency Syndromes
 IMMUNODEFICIENCY SYNDROMES
• Primary (or congenital) immunodeficiency disorders,
which are genetically determined.

• Secondary (or acquired) immunodeficiencies, which

may arise as complications of cancers, infections,
malnutrition, or side effects of immunosuppression,
irradiation, or chemotherapy for cancer and other
diseases.

• Immunodeficiencies are manifested clinically by

increased infections, which may be newly acquired or
reactivation of latent infections.
 Primary (Inherited) Immunodeficiencies

• Primary immunodeficiency diseases are inherited

genetic disorders that impair mechanisms of innate
immunity (phagocytes, NK cells, or complement) or
the humoral and/or cellular arms of adaptive
immunity (mediated by B lymphocytes and T
lymphocytes, respectively).

• These immunodeficiencies are usually detected in

infancy, between 6 months and 2 years of age, the
telltale signs being susceptibility to recurrent
infections.
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.

• Affected infants present with thrush (oral candidiasis), severe

diaper rash, and failure to thrive.

• Children with SCID are extremely susceptible to recurrent, severe

infections by a wide range of pathogens, including Candida
albicans, Pneumocystis jiroveci, Pseudomonas, cytomegalovirus,
varicella, and a whole host of bacteria.

• Without Hematopoietic Stem Cell transplantation, death occurs

within the first year of life.
X-Linked Agammaglobulinemia ( Bruton disease)
• Is characterized by the failure of pre–B cells to
differentiate into mature B cells with a resultant
absence of antibodies (gamma globulin) in the blood.

• Classically, the disease is characterized by a profound

reduction in the number of B cells in the blood and
secondary lymphoid organs and an absence of
germinal centers and plasma cells in these organs.

• T-cell numbers and responses may be normal.

• The disease usually does not become apparent until
about 6 months of age, as maternal antibodies that
were transported via the placenta are depleted.

• In most cases, recurrent bacterial infections of the

respiratory tract, such as acute and chronic pharyngitis,
sinusitis, otitis media, bronchitis, and pneumonia, call
attention to the underlying immune defect.

• Almost always, the causative organisms are

Haemophilus influenzae, Streptococcus pneumoniae, or
Staphylococcus aureus, organisms that are normally
opsonized by antibodies and cleared by phagocytosis.
 DiGeorge Syndrome (Thymic Hypoplasia)

• DiGeorge syndrome is caused by a congenital

defect in thymic development resulting in
deficient T-cell maturation.

• T cells are absent in the lymph nodes, spleen,

and peripheral blood, and infants with this
defect are extremely vulnerable to viral,
fungal, and protozoal infections.
 Ataxia telangiectasia
• is an autosomal-recessive disorder characterized by
abnormal gait (ataxia), vascular malformations
(telangiectases), neurologic deficits, increased
incidence of tumors, and immunodeficiency.

• The immunologic defects are of variable severity and

may affect both B cells and T cells.

• The gene responsible for this disorder encodes a

protein called ATM (ataxia telangiectasia mutated), a
sensor of DNA damage that activates cell cycle
checkpoints and apoptosis in cells with damaged DNA.
ACQUIRED IMMUNODEFICIENCY
SYNDROMES
Amyloidosis
 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
– AA (amyloid-associated) amyloid
– β-amyloid protein (Aβ)
Clinical Features
• The symptoms depend on the magnitude of the
deposits and on the sites or organs affected.

• Clinical manifestations at first are often entirely

nonspecific, such as weakness, weight loss,
lightheadedness, or syncope.

• Somewhat more specific findings appear later

and most often relate to renal, cardiac, and
gastrointestinal involvement.
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