Download Elements of Innate and Acquired Immunity

Autoimmunity and Disease
- When the integrity of self-tolerance is destroyed, to self, autoimmunity,
may develop.
- The consequences of autoimmunity may vary from minimal to catastrophic,
depending on the extent to which the integrity of self-tolerance has been
affected.
- A distinction should be made between autoimmune responses and
autoimmune disease, in which recognition of self antigen evokes
pathologic consequences that can involve antibody, complement,
immune complexes, and cell-mediated, immunity.
Causes of Autoimmune Disease
- Genetic susceptibility
 There is high incidence of autoimmune disease in monozygotic twins,
with a lower but still increased incidence in dizygotic twins and family
members compared to an unrelated population.
The pattern of inheritance is generally complex and indicates that
disease is polygenic. This means that no individual gene is sufficient to
elicit the disease and many genes may interact with one another.
 One gene family that is associated with autoimmune disease is the HLA
complex. While susceptibility to an autoimmune disease may be linked
to a specific MHC allele, eliciting the disease may require other genes
or certain environmental triggers.
 Studies in mice have shown that alterations in the expression of a
variety of non-HLA genes can interfere with many different pathways
of cellular function and contribute to autoimmunity.
1) Over expression or underexpression of genes involved in apoptosis
and cell survival.
2) Cytokines,
3) BCR singnaling pathways,
4) Costimulatory interactions,
5) Immune complexes,
6) All these factors lead to an autoimmune phenotype in mice.
 A deficiency in proapoptotic molecules "e.g Fas or Fas L" or
overexpression of antiapoptotic molecules "e.g bcl-2";( a gene produces
a protein that interfers with apoptosis) lead to diminished apoptosis and
result in an increased number of autoreactive B and T cells and
increased autoantibody production, especially the production of
antinuclear antibodies.
 T cell autoreactivity is often the consequence of over expression of
proinflammatory cytokines "such as IL-10", excessive costimulation
due to overexpression of costimulatory molecules "e.g B7, CD28", or a
deficiency of inhibitors of costimulatory interactions.
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 An alteration in the strength of the signal transduced by the B cell
receptor due to underexpression of signaling molecules, such as CD22
or overexpression of CD19 or CD45 is associated with autoantibody
production.
 Enhanced T cell help "e.g enhanced expression of CD40 or CD40L,
similarly leads to autoantibody production.
 Underexpression of proteins such as serum amyloid protein "SAP" that
are involved in clearance of apoptotic particles or decreased clearance
of immune complexes owing to a deficiency of an early component of
the classical pathway of complement "either C1q, C2, C3, or C4" leads
to autoantibody production.
 Target organ damage in autoimmune disease may also be genetically
determined. Murine models of autoimmune myocarditis reveal that
disease susceptibility and cardiac damage depend on strain specific
cardiac myosin antigen accessibility.
Environmental Susceptibility
- Several environmental factors, either infectious of noninfectious, can trigger
autoimmunity by inducing the release of sequestered antigens or molecular
mimicry or by polyclonal activation.
- Autoimmune myocraditis has been observed to arise in some cases following
a cardiac ischemic attack. It is believed that autoreactivity to cardiac antigens
develops as a consequence of exposure of sequestered antigens upon heart
damage.
- Autoimmunity may also arise when an antibody or T cell specific for
microbial antigens cross-reacts with a self antigen. This is referred to as
molecular mimicry.
- A T-dependent self antigen does not elicit an autoantibody response from a B
cell because here are no autoreactive T helper cells available to provide help,
since they have been either deleted or energized .
- A foreign antigen that contains an epitope that is similar to an epitope on a
self antigen can elicit an autoantibody response if it contains a T cell epitope
that is distinct from that of the self antigen (Fig 12.5) This is because the
foreign epitope activates T cells that have not been tolerized, and these T
cells can then provide help to the autoreactive B cells.
- Molecular mimicry is believed to play a role in the onset of rheumatic fever,
which sometimes follows a streptococcal infection. Autoantibodies to
cardiac myosin are believed to be elicited by cross-reactivity with a
streptococcal antigen.
- In autoimmune diabetes, a T cell that recognizes a peptide from glutamic
acid decarboxylase (an antigen in β-islet cells) has been shown to cross-react
with a peptide derived from coxsackievirus. This molecule mimicry can
initiate autoimmune disease following a microbial infection.
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- Microbial antigens can also induce autoimmunity by polyclonal activation.
Polyclonal activators may nonspecifically trigger many B cell or T cell
clones "including the autoreactive ones".
- Many bacterial and viral antigens act as superantigens. Which can activate
several different clones of T cells, regardless of their specificity, due to their
binding to Vβ gene domains that lie outside the peptide-binding domains.
- Conserved molecular structures on a large group of microorganisms
"pathogen-associated molecular patterns; PAMPs" act as polyclonal
activators of B cells.
Receptors, known as pattern recognition molecules, that bind these PAMPs
have been found on all B cells as well as other APCs. LPS can polyclonally
Activate mouse B cells including autoreactive B cells by interacting with a
receptor on the cell surface that is associated with TLR-4.
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There is hypothesis which suggests that innate signaling through toll
pathways may be a mechanism for activating anergic B cells that are
unresponsive to signaling via BCR cross-linking.
Some PAMPs can activate autoreactive B cells by interacting with TLRs
Expressed intracellularly, hypomethylated CpG DNA sequences commonly
found in bacterial DNA can be endocytosed by b cells following engagement
with BCR specific for DNA or proteins that form complexes with DNA.
Once inside the B-cell endosome, the CpG DNA sequences can interact with
TLR-9 and deliver a stimulatory signal. Similarly, RNA can activate antiRNA-specific B cells because it is recognized by endosomal TLR-7 and
TLR-8. A hypothesis suggests that innate signaling through toll pathway
may be a mechanism for activating anergic B cells that are unresponsive to
Signaling via cross- linking.
Triggers for Autoimmunity
- Hormones …. SLE is 10 times more common in women than in men due to
estrogens.
- Certain drugs can chemically alter the epitope of a self Ag to render it
immunogenic, resulting in autoimmunity. Some drugs ; chlorpromazine,
- Hydralazine, procainamide induce the production of antinuclear antibodies in
some individuals and have been linked on rare occasions to drug-induced
lupus.
- Inhibition or loss of suppressor T cells "Ts" can contribute to autoimmunity.
- Ts cells suppress the activation of CD4 + and CD8+ T cells. Loss of Ts favors
and increase in cell-mediated immunity, which can lead to T cell-mediated
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autoimmunity. Patients with diabetes and inflammatory bowel disease have
reduced numbers of Ts cells.
Examples of Autoimmune Diseases
A- Autoimmune Diseases in Which Antibodies Play the Predominant Role
in Mediating Organ Damage.
1- Autoimmune hemolytic anemia
- Hemoytic anemia is autoimmune when antibodies react with self
RBCs. The number of RBCs in the circulation is decreased.
- The destruction of RBCs can be attributed to two mechanisms;
1) * one involves the activation of the complement cascade and
eventual lysis of the cells.
* hemoglobinuria may be observed.
2) The second is by opsonization of RBCs facilitated by antibody
and C3b. RBCs are angulfed by macrophages whose receptors
for FC and C3b attach to the antibody-coated RBCs.
- Antibodies responsible for autoimmune hemolytic anemia are
divided into two groups:
1) Warm autoantibodies, they react optimally with RBCs at
37°C, they are IgG.
2) Cold agglutinins, attaches to RBCs only when the temperature
is below 37°C and dissociated from the cells when the
temperature rises above 37°C. they belong to IgM class. They
are highly efficient in activating the complement and causes
lysis of RBCs.
Hemolytic anemia may be induced by some drugs like
penicillin, α-methyldopa.
Sometimes cold agglutinins appear after infection by
Mycoplasma pneumoniae or viruses.
2- Myasthenia Gravis
- The target self antigen in this disease is acetylcholine receptor at
neuromuscular junctions.
- The autoantibody acts as an antagonist that blocks the binding of
acetylcholine to the receptor. This inhibits the nerve impulse from
being transmitted across the neuromuscular junction, resulting in
severe muscle weakness, manifested by difficulty in chewing,
swallowing, and breathing and eventually death from respiratory
failure "Fig. 12.7 “
- The disease appears to be linked to the thymus. Molecules crossreacting with acetylcholine receptor have been found on various
cells in the thymus such as thymocytes and epithelial cells.
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3- Graves Disease
- It
is
characterized
by
hyperactive
thyroid
gland
"hyperthyroidism".
- Antibodies directed against a hormone receptor may activate the
receptor rather than interfere with its activity.
- Patients develop autoantibodies against thyroid cell-surface
receptors for thyroid-stimulating hormone "TSH".
The interaction of these antibodies with the receptor activates the
cell in a mannar similar to the activation by TSH. Hence the
autoantibody behaves as an agonist "Fig. 12.7 “.
- The long-lasting stimulation by these antibodies causes
hyperthyroidism due to the continuous stimulation of the thyroid
gland.
4- Systemic Lupus Erythematosus "SLE"
- SLE gets its name "red wolf" from a reddish facial rash on the
cheeks, which is frequent early symptom.
- The disease attacks many organs of the body and causes fever, joint
pain, and damage to the CNS, heart and kidneys.
- SLE patients produce antibodies against several nuclear
components of the body "antinuclear antibodies; ANA".
Occasionally, antibodies are also produced against denatured
single-stranded DNA and against nucleohistones.
- Anti-double stranded DNA correlated best with the pathology of
renal involvement in SLE.
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- IgM antibodies are produced against single-stranded DNA, they
can undergo isotype switching to produce high affinity IgG.
- Double-stranded DNA may become trapped in the glomerular
basement membrane through electrostatic collagen, fibronectin, or
laminin.
- The bound DNA may trap circulating IgG anti-ds DNA antibodies
and lead to the formation of immune complexes. These complexes
may activate the complement and attract granulocytes.
- Anti ds-DNA antibodies may cross react with glomerular antigens.
the extent of the inflammatory reaction forms the basis of
classifying kidney pathology.
- The resulting glomerulonephritis leads to leakage of protein and
blood.
- As the condition becomes chronic, inflammatory CD4 + TH1 cells
enter the site and attract monocytes, which further contribute to the
pathologic lesions.
- SLE may result from exposure to some common environmental
factors such as u.v. light, hormones, infectious agents including
Epstine-Barr virus,EBV, have been proposed to play a role in the
etiology of the disease. Abs to viral Ags in EBV have been shown
to cross-react with some nuclear Ags. induction by drugs such as
penicillamine, chlorpromazine, hydrazine, procaiamide produce
antinuclear Abs in some individuals. Usually, drug-induced
autoimmune diseases are self-limiting: the disease disappears when
the drug is discontinued. There is increased risk of developing SLE
among family members.
B- Autoimmune diseases which T cells play a Predominant Role in Organ
Damage
1- Multiple sclerosis
- Multiple sclerosis "MS" involves demyelinization of CNS tissue
and is characterized by either a relapsing – remitting or a
progressive paralytic course.
It is considered to be a T cell-mediated autoimmune disease. The
lesions resemble the cellular infiltrates associated with TH1 cells
"DTH".
- HLA class II may be associated with the disease susceptibility.
2- Type 1 Insulin Dependent Diabetes Mellitus "IDDM"
- IDDM is a form of chronic inflammatory destruction of the insulinproducing β-islet cells of the pancreas.
- The major contributors to B cells destruction are cytotoxic T cells
and cytokines followed by antibodies.
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- Genetic factors include several genes in the MHC class II regions,
the insulin gene on chromosome 11, and at least 11 other non-HLA
linked diabetes susceptibility genes.
Some HLA class II haplotypes predispose for the disease, and
others are protective.
- About 50% of IDDM patients are HLA-DR3/DR4 heterozygotes.
- Individuals with HLA-DQB1-*0602 rarely develop the disease.
3- Hashimoto's Thyroiditis
- It is found in middle-aged women that leads to the formation of a
goiter, and eventual atrophy of the thyroid gland, which results in
hypothyroidism and destruction of thyroid function.
- The disease is mediated by T cells, but antibodies may contribute
to the disease process.
- Target antigens include thyroglobulin, microsomal antigen from
thyroid epithelial cells and antibodies to these antigens have been
found.
- Infiltration of mononuclear cells "B cells, T cells, macrophages"
lead to progressive destruction of thyroid follicles, the gland
attempts to regenerate and becomes enlarged.
When destruction continues, symptoms of hypothyroidism appear.
4- Rheumatoid Arthritis "RA"
- It is characterized by chronically inflammed synovium, densely
crowded with lymphocytes which results in the destruction of
cartilage and bone.
- The synovium is densely packed with dendritic cells, macrophages,
T, B, and NK cells and clumps of plasma cells, in some cases the
synovium develops secondary follicles.
- The pathology is a consequence of a mixture of
immunophathologic mechanisms, specially, antigen-antibody
complexes, complement, PMNLs, inflammatory CD4 + T cells,
CD8+ cytotoxic T cells, activated macrophages and NK cells.
- This angry-mix releases a variety of cytokines e.g. TNF α and IL-1,
degradative enzymes and mediators that destroy the integrity of the
cartilage.
- Chondrocytes "the cells of the cartilage" become exposed to the
immune system.
- Synovial fluid often accumulates in the joints of RA patients and
contains large numbers of PMNLs.
- Fibrin is deposited, cartilage is replaced by fibrous tissue, and the
joints fuses "ankylosis".
- IgM "rheumatoid factor-RF" …. Specific for determinants on the
FC portion of the patient's own IgG molecules.
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- RF is a useful marker of disease activity, since reduced levels of
serum RF are found during remission.
C- Autoimmune Diseases Arising from Deficiency in Components of
Complement
- Many patients with deficiencies in early components of
complement develop autoimmune diseases as SLE.
- Both the classical and alternative complement pathways inhibit the
formation of large immune complexes.
- Excessive immune complex formation may overwhelm
complement clearance mechanisms as in serum sickness.
- Deficiency in C4b and C3b results in failure to clear immune
complexes by macrophages.
- SLE occurs in > 80% of individuals with complete deficiency of
C1, C4, or C2.
Therapeutic Strategies
- Cytotoxic drugs such as cyclophosphamide and azathioprine that interfere
with DNA replication and indiscriminately destroy the body's white blood
cells.
- Cyclosporine A and FK506 prevent cellular activation.
- Anticytokine therapies. Blockade of TNFα by antibody or soluble receptor
for rheumatoid arthritis.
- Inhibition of IL-1 β by soluble receptor also seems a useful strategy in
rheumatoid arthritis. These immunomodulatory agents prevent an
inflammatory response.
- IFNβ is used in the treatment of multiple sclerosis.
- Monoclonal antibody of CD3 is being tested in new-onset autoimmune
diabetes.
- Costimulatory blockade to prevent interaction of B7 with CD28 appears
promising in RA and Psoriasis.
- Altered peptides that bind to the MHC groove but are not capable of
activating a given T cell, have been used to induce tolerance in rodent
models.
- T cell receptors have been administered to patients as an immunogen in an
effort to raise clonotype-specific cytolytic T cells.
- Generation of Ts cells in autoimmune individuals.
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 TABLE 12.1. Autoimmune Diseases
Autoimmune Disease
Class I
Ankylosing spondylitis
Reiter syndrome
Acute anterior uveitis
Hyperthyroidism (Graves)
Psoriasis vulgaris
Class II
Pheumatoid arthiritis
Sjogren syndrome
Systemic lupus
Erythematosus
Caucasian
Japanese
Celiac disease
Pemphigus vulgaris
Type I diabetes mellitus
Multiple sclerosis
Myasthenia gravis
Goodpasture syndrome
MHC Association
Allele
Strength of Association
B27
B27
B27
B8
Cw6
B*2702, -04, -05
Strong
Strong
Strong
Weak
Intermediate
DR4
DR3
DRB1*0401, -04, -05
Strong
Intermediate
DR3
DR2
DR3
DR4, DR6
DR4
DR3
DR2
DR3
DR2
Weak
Intermediate
Strong
Strong
Strong
Intermediate
Intermediate
Weak
Intermediate
DQA1*0501
DQB1*0302
DRB1*1501
 TABLE 12.2. Autoimmune Diseases, Target Autoantigens, and Effector Cells
Autoimmune Diseases
Autoantigen
Effector cells
Graves disease
Myasthernia gravis
Pernicious anemia
ANCA-associated vasculitis
Autoimmune hemolytic anemia
Idiopathic thrombocytopenic purpura
SLE
Sjogren syndrome
Scleroderma
Pemphigus vulgaris
Goodpasture syndrome
Rheumatoid arthritis
Hashimoto thyroiditis
Insulin dependent diabetes mellitus
Multiple sclerosis
TSH receptor
Acetylcholine receptor
Gastric parietal cells; intrinsic factor
Myeloperoxidase; serine proteinase
Rh blood group antigens
Platelet membrane protein, integrin
dsDNA; histones; ribonucleo proteins
(snRNPs)
Salivary duct antigens; SS-A, SS-B
nucleoproteins
centromeric proteins in fibroblasts;
nucleolar antigens; IgG; Scl-70
Desmoglein 3
Renal and lung basement membrane
collagen type IV
unknown cartilage antigen, IgG
(rheumatoid factor)
Thyroid proteins (thyroglobulin,
microsomal antigens, thyroid
peroxidase)
Pancreatic ß-islet cell antigen
Myelin basic protein
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B cells/autoantibody
B cells/autoantibody
B cells/autoantibody
B cells/autoantibody
B cells/autoantibody
B cells/autoantibody
B cells/autoantibody
B cells/autoantibody
Unknown
B cells;autoantibody
B cells;autoantibody
CD4+ T cells; CTLs; B cells/autoantibody
CD4+ T cells
CD4+ T cells; CTLs; B cells/autoantibody
CD4+ T cells