LESSON AUTOIMMUNE DISEASE

Introduction

> eAutommmune diseases are traditionally classified into two based on its target/s:

1. Organ-specific Autoimmune disease

> Targets a single tissue or a single organ

2. Non-organ-specific Autoimmune disease (Systemic autoimmune disease)

> Targets more than one tissue or organ

ENDOCRINE SYSTEM
1. Addison's Disease

> Caused by exogenous agent such as Mycobacterium tuberculosis or have an idiopathic cause,
believed to have an immunologic mechanism.
Autoantibodies directed against adrenal cells are believed to play main role in the pathogenesis of
Addison's disease.
The destruction of Adrenal glands decreases the production of Cortisol and Aldosterone.
The diagnosis is confirmed by demonstration of anti-adrenal antibodies by indirect
immunofluorescence test.

2. GRAVE’S DISEASE

> Graves’ disease is production of autoantibodies against thyroid-stimulating hormone (TSH)

receptor.
> The antibodies induce or stimulate unregulated activation of thyroid hormones.
> The autoantibodies, so produced against TSH receptors are called long-acting thyroid stimulator
(LATS), which is IgG in nature and can pass through the placental barrier and cause Graves'
disease in neonates

3. Hashimoto's Disease

> Hashimoto's thyroiditis is an autoimmune disease of the thyroid gland named after the Japanese
physician Hakaru Hashimoto.
> Characterized by the production of antibodies to two major thyroid proteins, thyroid peroxidase
and the hormone thyroglobulin.
These autoantibodies play a major role in the destruction of the thyroid gland, eventually causing
a decline in the output of thyroid hormones resulting in hypothyroidism.
3. Hashimoto's Disease - Goiter

> THI cells also contribute to the destruction of the thyroid gland in Hashimoto's thyroiditis: T cells
as well as B cells and macrophages-infiltrate the thyroid.
> Histologically, the thyroid often more closely resembles a lymphoid follicle with proliferating
germinal centers than a gland with epithelial cells lining the follicles.
> In some patients the gland, as it attempts to regenerate, may become enlarged, causing a goiter.

4. Type 1 Diabetes Mellitus

> Involves the beta cells of the islets of Langerhans against which there is formation of
autoantibodies.
> The autoimmune attack destroys the beta cells resulting to a decreased production of insulin and
consequently increased level of blood glucose.
Following the destruction of islet beta cells, there is abnormality in glucose metabolism resulting
in serious metabolic problems that include ketoacidosis and increased urine productions.

GASTROINTESTINAL

1. Autoimmune Hepatitis

Autoimmune Hepatitis 1
Antinuclear Autoantibodies (ANA) The target antigens of ANA are heterogenous and
not well defined. ANA have been shown to be
reactive with single- and double-stranded DNA,
centromeres, histones, chromatin, and cyclin A
Anti-Smooth Muscle Autoantibodies Directed against actin and other constituents of the
cytoskeleton, such as tubulin, vimentin, desmin, and
skeletin.
Autoimmune Hepatitis 2
Anti-Liver-Kidney Microsomal Type 1 Cytochrome P450-206
Autoantibodies
Anti-Liver Cytosol Type 1 Autoantibodies Folate-metabolizing enzyme formimino transferase
cyclodaminase (FTCD)
2. CELIAC DISEASE

> Celiac disease is an autoimmune disease affecting the small intestine and other organs. Celiac
disease is unique in that it is associated with a known environmental trigger-dietary gluten.
Gluten is a protein complex found in wheat, barley, and rye that is poorly digested by the upper
gastrointestinal system. It contains an alcohol-soluble component called gliadin that is rich in the
amino acids glutamine and proline.
Glidin is resistant to digestive enzymes in the stomach, pancreas, and small intestine and
therefore remains intact in the lumen, or space within the intestines, after ingestion. If there is an
increase in the permeability of the intestinal walls, possibly as a result of an infection, undigested
gliadin is able to pass through the epithelial barrier of the intestine and trigger an inappropriate
immune response.
The immunogenicity of gliadin is enhanced when it is acted on by tissue transglutaminase (ITG),
an intestinal enzyme that converts the glutamine residues in gliadin to glutamic acid

3. Primary Biliary Cirrhosis

> An autoimmune liver disease characterized by immune-mediated destruction of small intrahepatic

bile ducts, leading to chronic cholestasis and fibrosis that can eventually result in cirrhosis and
liver failure.

NERVOUS SYSTEM
1. Multiple Sclerosis

> Demyelination or destruction of the myelin sheaths surrounding central nervous system.
> Individuals with disease produce autoreactive T cells that take part in the formation of
inflammatory lesions along the myelin sheath of nerve fibers.
> The cerebrospinal fluid (CSF) of patients of MS reveal sensitized T lymphocytes, which infiltrate
the brain tissue and cause characteristic inflammatory lesions destroying the insular covering
(myelin sheath) of the nerve fibers leading to a number of neurologic dysfunctions.

2. Myasthenia Gravis

> Myasthenia gravis is formation of antibodies against acetylcholine receptors present in the motor
end-plates of muscle, which blocks the normal binding of acetylcholine and also induces
complement-mediated degradation of the receptors, resulting in progressive weakness of the
muscle
URINARY SYSTEM
1. Post-streptococcal Glomerulonephritis

> An immune-mediated glomerulonephritis associated with extrarenal bacterial infections.

> Anti-streptolysin O and Anti-DNAse-B antibody titers are usually elevated.
> The streptococcus bacteria do not attack the kidney directly, but an infection may stimulate the
immune system to overproduce antibodies, which are circulated in the blood and finally deposited
in the glomeruli, causing damage

2. Good Pasteur's Syndrome

> Characterized by the presence of autoantibody to an antigen in the basement membranes in the
glomeruli of the kidneys and alveoli of the lungs.
> Autoantibodies produced in Goodpasture's syndrome are known to be specifically directed
against the non-collagenous domain of the alpha-3 chain of type IV collagen.
> This autoantibody reacts with collagen in the glomerular or alveolar basement membranes and
causes damage by type II hypersensitivity.

NON-ORGAN SPECIFIC AUTOIMMUNE DISEASE

1. Systemic Lupus Erythematosus

> Autoantibodies (IgG, IgM and IgA) are formed primarily against the components of
deoxyribonucleic acid (DNA), but also can be made against blood cells [red blood cells (RBCs),
platelets and leukocytes], clotting factors, neurons and histones.
> When immune complexes of autoantibodies with various nuclear antigens are deposited along the
walls of small blood vessels, a type II hypersensitivity reaction develops.
> Laboratory diagnosis of SLE consists of demonstrations of antinuclear antibodies

2. Rheumatoid Arthritis

» Rheumatoid arthritis affects mainly the joints of the hands and feet although it can extend to other
tissues.
> Characterized by inflammation and destruction of cartilage in the joints. causing deformities.

RHEUMATOID FACTOR ANTI-CYCLIC CITRULLINATED PROTEINS

» IgM antibody and is directed against the » These antibodies can react with citrulline-
FC portion of IgG. containing components of the matrix,
>» It has been postulated that RFs may play a including filaggrin, keratin, fibrinogen, and
role in the pathogenesis of RA by vimentin, and are thought to correlate with
increasing macrophage activity and the pathogenesis of RA.
enhancing antigen presentation to T cells
by APCs.
3. WEGENER’S GRANULOMATOSIS

> In Wegener granulomatosis, an inciting antigen (perhaps proteinase 3 [PR3]) activates dendritic
cells.
> Antigen-loaded activated dendritic cells travel from the lungs to peripheral lymph nodes and
present antigen to naive CD4+ T cells, which differentiate into activated antigen-specific T cells.
Interleukin 12 (IL-12) produced by activated dendritic cells skew the T cells to a type 1 helper
(Tp1) phenotype.
Proliferating activated T, 1 cells return to the lungs where antigen persists. Interferon y (INF-y)
and tumor necrosis factor a (TNF-a) secreted by TH1 cells (predomimantly CD4+ CD28-) induce
macrophage migration and maturation and eventual granuloma formation and tissue destruction.
Chronic T cell activation may promote affinity maturation of autoreactive B cells that results in
secretion of PR3-antineutrophil cytoplasmic antibodies (ANCAs) in the granulomas.b

4. SCLERODERMA (SYSTEMIC SCLEROSIS)

> A multiple connective tissue disorder of inknown etiology in which vascular lesions and tissue
fibrosis are prominent features.
> Scl patients spontaneously produce autoantibodies against nuclear, nucleolar, mitochondrial, and
other cytoplasmic antigens
> Scleroderma can be phenotypically classified into two broad clinical categories

1. Diffuse cutaneous Scl (dcScl)

2. Limited cutaneous Scl (IcScl)

5. Sjogren's Syndrome

> A chronic inflammatory exocrinopathy, an autoimmune disease marked by dryness of the yes,
mouth, and other mucous membranes.
The disease may evolve from localized exocrine gland involvement to a systemic disorder, as
well as to B cell lymphoproliferative transformation.
The affected salivary or lacrimal glands are infiltrated with aggregates of lymphocytes.
Antinuclear autoantibodies in SS are normally restricted to SS-A/Ro and SS- B/La.
 INTRODUCTION
>» Immunodeficiencies are disorders in which a part of the body's immune system is missing or
dysfunctional.
>» Immunodeficiencies are divided into two major categories:

PRIMARY IMMUNODEFICIENCY SECONDARY IMMUNODEFICIENCY

May be hereditary or acquired, in which the | The immune deficiency is a result of other diseases
deficiency is the cause of disease or conditions.

1. Bruton's Agammaglobulinemia

> Also known as Bruton's tyrosine kinase (Btk) deficiency or X-linked agammaglobulinemia
(XLA).
> The major defect lies in the inability of pre-B cells, which are present at normal levels in the bone
marrow, to develop into mature B cells due to deficiency of an enzyme called the Btk in B-cell
progenitor cells
> Lack of the enzyme apparently causes a failure of immunoglobulin VH gene rearrangement.

2. Transient hypogammaglobulinemia of infancy

> When infants are approximately 5-6 months of age, passively transferred maternal IgG
disappears, and IgG production by the infant begins to rise.
> Premature infants may have transient IgG deficiency if they are not yet able to synthesize lg.
> Although treatment is usually not necessary, affected infants need to be identified, as they should
not be given immunizations during this period.

3. Common Variable Immunodeficiency

> Patients have markedly decreased serum IgG and IgA levels, with normal or low IgM and normal
or low peripheral B-cell numbers.
> The cause of the disease, which affects both males and females, is unknown
> Characterized by a failure in the maturation of B cells into antibody- secreting cells.

4. Selective IgA Deficiency

The most common congenital immunodeficiency.

VVV WV

Most patients with a deficiency of IgA are asymptomatic.

If the serum IgA is lower than 5 mg/mL, the deficiency is considered severe.
Although the genetic defect has not been established, it is hypothesized that lack of IgA is caused
by impaired differentiation of lymphocytes to become I[gA-producing plasma cells.

5. Selective IgM Deficiency

 >» It is a rare disorder associated with the absence of IgM and normal levels of other
immunoglobulin classes.
» The cause of selective IgM deficiency is unknown.
> Asa developmental disorder, absence of IgM with normal IgG and IgA contradicts the theory of
sequential immunoglobulin development.

6. Selective IgG Deficiency

» Deletion of constant heavy chain genes or abnormalities of isotype switching may result in
deficiencies of one or more of the IgG subclasses
> Most IgG antibodies directed against protein antigens are of the IgGl and IgG3 sub-classes,
whereas most IgG antibodies against carbohydrate antigens are IgG2 or IgG4.
¥ Deficiencies involving IgG1 or IgG3 lead to a reduced capability of responding to protein
antigens such as toxins
¥ Deficiencies of IgG2 can result in impaired responses to polysaccharide antigens, which
cause recurrent infections with polysaccharide-encapsulated bacteria such as
Streptococcus pneumoniae and H. influenzae.

T-CELL DEFICIENCY
1. DiGeorge Anomaly

» A developmental abnormality of the third and fourth pharyngeal pouches that affects thymus
development in the embryo.
> The immunodeficiency associated with the DiGeorge anomaly is a quantitative defect in
thymocytes.
» Not enough mature T cells are made, but those that are present are functionally normal.
> The immunodeficiency of DiGeorge syndrome can be treated with fetal thymus transplantation.

2. Purine Nucleoside Phosphorylase Deficiency

>» PNP deficiency affects an enzyme involved in the metabolism of purines.

PNIP — —=
~ Purine 1 hypoxanthine —+ tric acid/

>» The number of T cells progressively decreases because of the accumulation of deoxyguanosine
triphosphate, a toxic purine metabolite.
> The levels of immunoglobulins are generally normal or increased.

1. Nezelof's Syndrome

>» Animmune deficiency in which there is thymic hypoplasia and T-cell deficiency with selectively
elevated, decreased or normal levels of immunoglobulin.
2. Ataxia Telangiectasia

> A rare autosomal recessive syndrome characterized by cerebellar ataxia and telangiectasias
especially on the earlobes and conjunctiva.
> There is a mutation in AT gene located on chromosome 11, region q22.

¥ This abnormality results in a defective kinase involved in DNA repair and in cell cycle
control.

Patients’ lymphocytes often exhibit chromosomal breaks and other abnormalities involving the
TCR genes in T cells and immunoglobulin genes in B cells.

3. Wiskott-Aldrich Syndrome

> A rare X-linked recessive syndrome that is defined by the triad of immunodeficiency, eczema,
and thrombocytopenia.
There is mutation in the X-linked gene coding for the Wiskott-Aldrich syndrome protein (WASP)
Due to mutation, the cytoskeletons of both T and B cells cannot effectively reorganize in response
to stimuli
The immune defects are variable, but both T and B cells are functionally abnormal, with T-cell
numbers particularly decreased.

4. Severe combined immunodeficiency (SCID)

> The most serious of the congenital immunodeficiencies is severe combined immunodeficiency
(SCID).
> SCID is actually a group of related diseases that all affect T- and B-cell function but with
differing causes.
> The immune system is so compromised that live attenuated vaccine [Sabin polio, bacille
Calmette-Guérin (BCG)] can cause infection and disease.

Disorders of Phagocytosis
> Disorders of phagocytosis may be due to intrinsic or extrinsic defects.
> Intrinsic defects are the defects within phagocytic cell (e.g. enzyme deficiencies).
> Extrinsic defects are due to:

1. Deficiency of opsonic antibody, complement and other factors promoting phagocytosis.

2. Effect of drugs.

3. Antineutrophil autoantibodies.
1. Chronic Granulomatous Disease

CGD is the most common and best characterized of the neutrophil abnormalities.
Several specific molecular defects have been described in this syndrome, all of which result in the
inability of the patient's neutrophils to produce the reactive forms of oxygen necessary for normal
bacterial killing.
Three different autosomal recessive genes are involved and all affect subunits of nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase.

3. Chédiak-Higashi syndrome

> An autosomal recessive disease characterized by abnormal giant granules and organelles due to a
mutation of the LYST gene
> This gene codes for a protein that may have a role in organelle protein trafficking
> Neutrophils show diminished intracellular killing of organisms, the result of both defective
degranulation and impaired fusion of lysosomes with phagosomes.

4. Leukocyte Adhesion Deficiency

> In leukocyte adhesion deficiency condition, there is deficiency of cell surface molecules
belonging to the integrin family of proteins, which functions as adhesion molecules and are
required to facilitate cellular interaction.

5. Job's Syndrome (Hyper IgE Syndrome)

> Hyper IgE syndrome is an immune deficiency caused by a genetic mutation in either STAT3
(autosomal dominant, also known as Job's syndrome) or DOCK8 (autosomal recessive).
> There may be other mutations in other genes that are not known at this time.
> Serum immunoglobulins are normal except for elevated IgE

6. Lazy Leukocyte Syndrome

> In lazy leukocyte syndrome, basic defect is in chemotaxis and neutrophil mobility.
> Bone marrow study reveals enough neutrophils, yet there is neutropenia with poor leukocyte
response to chemical and inflammatory stimulation