Chapter 28: Autoimmune Disorders

What is autoimmunity?

- Autoimmunity represents a breakdown of the

immune system’s ability to discriminate
between self and non-self.
- Autoimmune disorders remain among the most
poorly understood and poorly recognized of any
category of illnesses.
- The term autoimmune disorder is used when
demonstrable immunoglobulins
(autoantibodies) or cytotoxic T cells display
specificity for self antigens, or autoantigens,
and contribute to the pathogenesis of the
disorder

FACTORS INFLUENCING DEVELOPMENT OF

AUTOIMMUNITY:

1. Genetic Factors – Although a direct genetic cause has not been established in autoimmune
disease, there is a tendency for familial aggregates to occur. In addition, there is a tendency for
more than one autoimmune disorder to occur in the same individual
2. Patient Age – The incidence of autoantibodies, however, increases steadily with age, reaching a
peak at around 60 to 70 years.
3. Exogenous Factors – Ultraviolet radiation, drugs, viruses, and chronic infectious disease may all
play a role in the development of autoimmune disorders. These factors may alter antigens,
which the body then perceives as non-self antigens.

SELF RECOGNITION (Tolerance)

- The lack of immune response to self antigens and is initiated during fetal development (central
tolerance) by the elimination of cells with the potential to react strongly with self antigens
o Peripheral tolerance – is a process involving mature lymphocytes and occurs in the
circulation
o Central tolerance – develops in the thymus during fetal life
- Self-recognition (tolerance) is induced by at least two mechanisms involving contact between
antigen and immunocompetent cells:
o Elimination of the small clone of immunocompetent cells programmed to react with the
antigen (Burnet’s clonal selection theory)
o Induction of unresponsiveness in the immunocompetent cells through excessive antigen
Major Autoantibodies

- Major autoantibodies can be detected in different disorders.

- Common autoantibodies include thyroid, gastric, adrenocortical, striated muscle, acetylcholine
receptor, smooth muscle, salivary gland, mitochondrial, reticulin, myelin, islet cell, and skin
- Antibodies to antinuclear antibodies (ANAs) include deoxyribonucleic acid (DNA), histone, and
nonhistone protein antibodies

ORGAN-SPECIFIC AND MIDSPECTRUM DISORDERS

CARDIOVASCULAR DISORDERS

Primary immunologic diseases of the blood vessels are termed vasculitis; those of the heart are
termed carditis.

o Vasculitis
 Vasculitis occurs as a primary disease process or as a secondary manifestation of
another disease (e.g., RA)
 Vasculitis is characterized by inflammation within blood vessels
 Ischemia causes the major manifestations of the vasculitic syndromes and
determines the prognosis
o Carditis
 Presence of inflammatory cells within the myocardium resulting from immune
sensitization to endogenous or exogenous cardiac antigens
 Carditis can be caused by a variety of conditions, including acute rheumatic
fever, Lyme disease, and cardiac transplant rejection.
 Primary idiopathic myocarditis is an autoimmune disease characterized by
infiltration of the heart by macrophages and lymphocytes.
 Antimyocardial antibodies appear to be strongly cross-reactive with
streptococcal antigens, but they are not toxic to heart tissue unless the latter is
damaged
 The presence of myocardial antibodies, however, is diagnostic of Dressler’s
syndrome (cardiac injury) or rheumatic fever.
COLLAGEN VASCULAR DISORDERS
o Progressive Systemic Sclerosis (Scleroderma)
 Scleroderma is a collagen vascular disease of unknown cause that assumes
various forms.
 Eosinophilic fasciitis may be a variant of scleroderma
 Manifestation is Reynaud’s Phenomenon
 Scleroderma is characterized by fibrosis in the skin and internal organs and by
arterial occlusions with a distinct proliferative pattern
 Subset of scleroderma with CREST syndrome (calcinosis, Raynaud’s
phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia)
 Systemic sclerosis is a chronic multisystem disorder that causes thickening of
the skin (scleroderma) and involves other organ systems
 o Eosinophilia-Myalgia Syndrome
 Agent causing eosinophilia-myalgia syndrome (EMS) may develop illness
 The most important predictor of EMS is the ingestion of contaminated L-
tryptophan.
ENDOCRINE GLAND DISORDERS: THYROID DISEASE

There are two major forms of autoimmune thyroid disease, chronic autoimmune thyroiditis and
Graves’ disease. Lymphoid (Hashimoto’s) chronic thyroiditis is a classic example of an organ-specific
autoimmune disorder

o Lymphoid (Hashimoto’s) Chronic Thyroiditis

 Producing hypothyroidism
 Most common cause of sporadic goiter
 Characteristically, there is a firm, diffusely enlarged, nontender thyroid gland
that may be lobulated
 Hypothyroidism, is a common late sequela of lymphoid thyroiditis, and patients
are usually euthyroid when first seen by a physician
 Immunologic Manifestations: Antibodies to thyroid constituents may be
observed in these patients. Antibodies to the following constituents may be
demonstrated serologically
 Thyroglobulin – first antibody discovered against a thyroid protein,
thyroglobulin
 Thyroid microsome – Antibodies directed against thyroid microsomes,
antithyroid microsomal antibodies, or antithyroperoxidase antibodies
(TPO Abs)
 Second Colloid Antigen (CA2 antigen) – CA2 antigen is directed against
a colloid protein and can be detected by immunofluorescent
examination
 Thyroid Membrane Receptors – The thyroid membrane receptors are a
group of immunoglobulin G (IgG) antibodies that interact with receptors
on thyroid membranes
 Thyronine (T4) and Triiodothyronine (T3)
o Graves’ Disease
 A form of hyperthyroidism.
 Laboratory chemistry assays usually demonstrate low TSH and elevated free T4
levels
PANCREATIC DISORDERS
o Insulin-dependent Diabetes Mellitus
 Type 1 diabetes mellitus (T1D), is a disorder of deficient insulin production
caused by immune destruction of the B cells of the pancreatic islets
 T1D was previously called juvenile-onset diabetes
 Responsible for initiating the immune response to the islets that results in islet
cell autoantibodies and B cell destruction
 Patients with T1D have the following types of autoantibodies:
 Insulin autoantibodies (IAAs)
  Glutamic acid decarboxylase (GAD) autoantibodies
 Islet cell antigen-2 (IA-2)
o Latent Autoimmune Diabetes in Adults (LADA)
 Is now recognized as a slowly developing form of autoimmune diabetes found in
patients who are older than 35 years of age
 LADA is frequently misdiagnosed as type 2 diabetes.
 LADA patients progress more rapidly to insulin dependence (T1D) than the
typical T2D patient.
o Autoimmune Pancreatitis
 A heterogeneous disease
 Immunologic abnormalities include the following:
 Hypergammaglobulinemia
 Elevated serum IgG4 concentrations
 Autoantibodies against carbonic anhydrase II
 Increased number of CD4+ T lymphocytes in peripheral blood
o Adrenal Glands
 Idiopathic adrenal atrophy is the primary cause of Addison’s disease.
 Idiopathic Addison’s disease is usually diagnosed in patients because of low
serum cortisol levels in the presence of elevated  levels of corticotropin.
o Pituitary Gland
 Sheehan’s syndrome, lymphocytic adenohypophysitis, is a disorder that causes a
rapid decline in pituitary function.
o Parathyroid Gland
 It is associated with complement-mediated cytotoxicity of parathyroid cells,
indicating a specific immune response to the parathyroid
 Idiopathic hypoparathyroidism occurs as a childhood disorder in type I
polyglandular syndrome and, less often, as an isolated disorder in adults
o Polyglandular Syndromes
 Three syndromes of associated endocrinopathies have been defined as the
polyglandular syndromes
 Type I polyglandular syndrome involves mucocutaneous candidiasis
and associated endocrinopathies that begin in early childhood
 Type II polyglandular syndrome involves the combined occurrence of
IDDM or autoimmune thyroid disease with Addison’s disease
 Type III polyglandular syndrome is defined as autoimmune thyroid
disease occurring with two other autoimmune disorders, including
IDDM, pernicious anemia, and a nonendocrine, organ-specific
autoimmune disorder, such as myasthenia gravis
EXOCRINE GLAND DISORDERS
o Sjögren’s Syndrome
 A chronic inflammatory disease of unknown cause that affects lacrimal, salivary,
and other excretory glands.
 It results in keratoconjunctivitis sicca and xerostomia.
GASTROINTESTINAL DISORDERS
o Atrophic Gastritis and Pernicious Anemia
 A malfunctioning immune system can target the stomach lining, resulting in
autoimmune gastritis, characterized by chronic inflammation of the gastric
mucosa.
 Persons with autoimmune gastritis may progress to pernicious anemia (PA)
 characterized by the presence of serum autoantibodies against gastric parietal
cells, H+/K+−ATPase (proton pump), and the cobalamin-absorbing protein,
intrinsic factor.
 Atrophic gastritis, which almost always accompanies PA
o Autoimmune Liver Disease
 Hypergammaglobulinemia, prominent lymphocyte and plasma cell inflammation
of the liver, and the presence of one or more circulating tissue antibodies are
typically manifested
 Autoimmune hepatitis (AIH), formerly known as chronic active hepatitis is an
inflammatory condition most common in young women
o Idiopathic Biliary Cirrhosis
 A slowly progressive disease that starts as an apparently noninfectious
inflammation in the bile ducts of young to middle-aged women.
 Patients exhibit increased serum IgM, depression of cellular immunity, with
prominent decreases in suppressor T cells common, and associated
autoimmune disorders.
o Inflammatory Bowel Disease
 Inflammatory bowel disease (IBD) is the collective name given to Crohn’s
disease (CD) and ulcerative colitis (UC)
 more common among Ashkenazi Jews than other groups
 The inflammation seen in IBD patients has been linked to the following:
 Presence of increased levels of inflammation-promoting cytokines
 Protein molecules used by cells of the immune system to communicate
with each other
 Studies have suggested that one cytokine, IL-12, is a crucial mediator of this
disease.
 The following serologic markers have been found to be useful in the diagnosis
and differentiation of Crohn’s Disease (CD) and Ulcerative Colitis (UC):
 Deoxyribonuclease (DNase I)
 Anti–Saccharomyces cervisiae antibody (ASCA)
 Pancreatic antibody
 Anti–outer membrane porin from Escherichia coli (anti-OmpC)
o Celiac Disease
 Lifelong autoimmune intestinal
disorder found in individuals who
are genetically susceptible
 
Gluten is the common name for the offending proteins in specific cereal grains
that are harmful to those with celiac disease.
o Other Gastrointestinal Tract Immunologic Disorders
 Examples of other immunologic disorders related to the GI and hepatobiliary
tracts include
 GI allergy,
 Whipple’s disease,
 Immunoproliferative intestinal disease (alpha heavy-chain disease), and
 Infectious hepatitis.
AUTOIMMUNE HEMATOLOGIC DISORDERS

Various hematologic conditions can be caused by alloantibodies and autoantibodies.

o Autoimmune Hemolytic Anemia

 Autoimmune hemolytic anemia can be classified into the following four groups:
 Warm-reactive Autoantibodies (most common)
 Cold-reactive Autoantibodies (<20% of cases)
 Paroxysmal Cold Hemoglobinuria (rare)
 Drug-induced Hemolysis (<20% of cases)
 Warm Autoimmune Hemolytic Anemia –
 This anemia is associated with antibodies reactive at warm
temperatures (i.e., 37° C [98.6° F]).
 In warm autoimmune hemolytic anemia, negligible serum autoantibody
exists because the antibody reacts optimally at 37° C (98.6° F ) and is
being continuously adsorbed by red blood cells (RBCs) in vivo.
 Cold Autoimmune Hemolytic Anemia –
 Cold hemagglutinin disease (CHAD), acute or chronic, is the most
common type of hemolytic anemia associated with cold-reactive
autoantibodies.
 The acute form is often secondary to Mycoplasma pneumoniae
infection or lymphoproliferative disorders such as lymphoma.
 In CHAD, a cold-reactive IgM autoantibody reacts with RBCs in the
peripheral circulation when the body temperature falls to 32° C (89.6° F)
or lower and binds complement to the cells
 Paroxysmal Cold Hemoglobinuria –
 Previously associated with syphilis, paroxysmal cold hemoglobinuria is
now seen more often as an acute transient condition secondary to viral
infections, particularly in young children.
 This IgG autoantibody, a biphasic hemolysin, can be demonstrated by
performing the classic Donath-Landsteiner test
 Drug-Induced Hemolysis –
 Coating of RBCs demonstrated by a positive direct anti–human globulin
test (DAT)
 The reactivity has been described as being caused by four basic
mechanisms:
 o Drug Adsorption
o Immune Complexing
o Membrane Modification
o Autoantibody Formation
o Idiopathic Thrombocytopenic Purpura
 Now also known as immunologic thrombocytopenic purpura (ITP).
 Patients with ITP usually demonstrate petechiae, bruising, menorrhagia, and
bleeding after minor trauma.
 ITP may be acute or chronic
 However, most thrombocytopenic conditions can be classified into the following
three major categories:
 Decreased production of platelets
 Disorders of platelet distribution
 Increased destruction or use of platelets
 Decreased platelet production may result from invasion of the bone marrow by
neoplastic cells and is usually not associated with an immunologic cause
o Pernicious Anemia
 A megaloblastic anemia characterized by a variety of hematologic and chemical
manifestations
 PA is caused by a deficiency of vitamin B12 that results from the patient’s
inability to secrete intrinsic factor.
o Amyotrophic Lateral Sclerosis
 Along with Alzheimer’s disease and Parkinson’s disease, ALS is one of the so-
called degenerative diseases of the aging nervous system.
 There also seems to be an increased frequency of antibodies to a neuronal
ganglioside, GM-1.
 It has also been suggested that ALS patients have a higher incidence of
lymphoproliferative disease—lymphoma, Waldenström’s macroglobulinemia,
and myeloma
o Inflammatory Polyneuropathies
 includes the acute disorder Guillain-Barré syndrome (GBS)
 Greatly elevated immunoglobulin levels in the cerebrospinal fluid (CSF)
o Myasthenia Gravis
 A disorder of the neuromuscular
junction characterized by
neurophysiologic and immunologic
abnormalities.
 This suggests that antibody to
AChR is capable of increasing the
normal rate of degradation,
resulting in fewer available receptors.
o Multiple Sclerosis
 Multiple sclerosis (MS) is the most common demyelinating disorder of the CNS
related to abnormalities of the immune system.
 The other forms of MS are as follows:
 Primary progressive
 Secondary progressive
 Progressive relapsing
RENAL DISORDERS

It is generally accepted that most immunologically mediated renal diseases fall into several
categories

o Renal Disease Associated with Circulating Immune Complexes

 Renal diseases associated with circulating immune complexes are caused by
nonrenal antigens and their corresponding antibodies.
o Membranoproliferative Glomerulonephritis
 Another type of glomerular disease, membranoproliferative glomerulonephritis,
 believed to be caused by non-immunologically activated complement
o Renal Disease Associated with Anti-Glomerular Basement Membrane Antibody
 Anti–glomerular basement membrane (GBM) antibodies are directed against
GBM of the glomerulus of the kidney
 High antibody titers of anti-GMB are suggestive of Goodpasture’s disease, early
SLE, or anti-GBM nephritis.
 The absence of antibodies, however, does not rule out Goodpasture’s disease.
o Tubulointerstitial Nephritis
 Tubulointerstitial nephritis involving the renal tubules has been associated with
a variety of causes, including immune complex–mediated disease
 Precipitating factors can include drugs and possibly infection, as well as the
involvement of transplanted kidneys.
SKELETAL MUSCLE DISORDERS
o Inflammatory Myopathy
 Polymyositis and dermatomyositis are the most common expressions of a group
of chronic inflammatory disorders and can be subclassified into the following six
categories:
 Primary idiopathic polymyositis
 Primary idiopathic dermatomyositis
 Polymyositis or dermatomyositis associated with neoplasia
 Childhood polymyositis or dermatomyositis
 Dermatomyositis or polymyositis associated with collagen vascular
disease
 Polymyositis or dermatomyositis associated with infections
 The term dermatomyositis is used for the disorder when the clinical features of
disease are accompanied by characteristic inflammatory manifestations in the
skin.
 There is a preponderance of B lymphocytes and an increased CD4+/CD8+ T cell
ratio.
 SKIN DISORDERS

A wide variety of autoimmune disorders

are associated with skin manifestations

- Anti-skin (dermal-epidermal)
antibodies are present in more than
80% of patients with bullous pemphigoid, but the absence of antibodies does not rule out the
disorder