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“Immunology” Lecture #23

Autoimmune diseases
Most healthy individuals produce some autoantibodies, although these are usually very low level and low affinity
and require sensitive tests for their detection. Higher-affinity autoantibodies detectable with routine clinical
tests are also found in some healthy people, especially women and the elderly.

How Autoimmune disease Develops

 Autoimmunity can be defined as adaptive immune responses with specificity for self antigens.
 Natural antibodies secreted by B1 cells have a number of different activities
 Natural antibodies bind with low affinity to antigens present on a large variety of bacteria. This activates
complement and helps clear invading bacteria rapidly. Thus natural antibodies act like molecules of the
innate immune system—they do not rely on genetic recombination, and they are present before an
infection starts.
 Natural antibodies cross-react with the inherited A and B antigens of red cells. Unless they have
inherited either A or B antigens, individuals make IgM anti-A and anti-B antibodies, even if they have
never been exposed to red cells from anotherperson. Humans also have natural antibodies against
sugars expressed on cells of other animal species.
 Another consequence of their low specificity is that natural antibodies can also bind to a series of
normal cellular constituents, such as nuclear proteins and DNA. This explains why some healthy people
have antinuclear antibodies. The autoantigen-binding ability of natural antibodies may be an accidental
consequence of cross-reactivity, but these antibodies may have a role, such as clearing up cellular
debris.

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The initiation of autoimmune disease

 Autoimmune disease occurs when autoreactive T cells or autoantibodies cause tissue damage through
hypersensitivity reaction types II through IV
 Autoimmune diseases are common and tend to be chronic diseases that usually last months or years. They
can affect any organ system and occur at any age. Understanding how autoimmune diseases arise helps us
diagnose, treat, and even prevent these problems.
 There is evidence that T cells initiate autoimmune disease as follows:
o Even autoimmune diseases caused by IgG-mediated mechanisms (hypersensitivity types II and III)
require T-cell help for affinity maturation to produce pathogenic (diseasecausing) antibodies.
o Transfer of T cells from an animal with autoimmune disease to a healthy animal can transfer disease.
o Autoimmune diseases are often linked to specific major histocompatibility complex (MHC) genes, which
regulate T cells but not B cells.
 There is no evidence that the B1 cells, which secrete harmless natural antibodies, can also produce the high-
affinity, specific antibodies that can cause autoimmune disease without T-cell help.
 For T cells to mediate autoimmune disease, they need to overcome tolerance mechanisms.

How T cells are tolerized to autoantigen?

 Tolerance prevents the immune system from responding to specific antigens. Checkpoints during central and
peripheral tolerance have evolved to prevent T cells from mediating autoimmunity.
 T cells are initially made tolerant of autoantigens in the thymus; this is central tolerance: Any T cell that
binds at high affinity to self peptide in the thymus will be deleted by negative selection in a process referred
to as central tolerance.
 However, it is not possible for every self peptide to be expressed in the thymus, so some autoreactive T cells
may escape negative selection.
 For potentially autoreactive T cells that have escaped to the periphery, there are more potential blocks that
normally prevent stimulation:

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The breakdown of T-Cell Tolerance “Failure of central tolerance”:

 Less expression of self Ags in the thymus: If there's a reduced presentation of self-antigens in the thymus,
some autoreactive T cells may go undetected.
 MHC alleles less efficient in presenting self Ags to T cells
 Peripheral tolerance breakage, SLE and DNA release if not removed by Complement: If complement-
mediated clearance of self-DNA is impaired, it can contribute to the breakdown of peripheral tolerance.
 Privileged sites breakage: Certain tissues or organs in the body are considered "privileged sites" because
they have restricted access to the immune system. If immune privilege is compromised, it can lead to
autoimmune responses against these tissues.
 APC present self Ags following infection: Antigen-Presenting Cells (APCs) can present self-antigens to T cells
in the context of an infection. This can lead to T cells mistaking self-antigens for foreign antigens and
initiating an autoimmune response.
 Molecular mimicry is a phenomenon where pathogens have antigens that resemble self-antigens, leading to
cross-reactivity. In the case of rheumatic fever, the immune system's response to streptococcal bacteria can
cross-react with heart tissue due to molecular mimicry.
 Failure of Treg, IPEX, and Foxp3 mutation: Regulatory T cells (Tregs) play a crucial role in suppressing
immune responses to self-antigens. If Tregs fail to function properly or if there are mutations in genes like
Foxp3 (associated with Tregs), it can lead to autoimmune responses.
 Both genetic and environmental factors are required for autoimmune disease to develop.

Genetic Factors and Loss of Tolerance

• Rare genetic diseases cause autoimmunity. For example, in autoimmune polyendocrinopathy candidiasis
ectodermal dysplasia (APECED) syndrome >>> the AIRE gene is mutated and central tolerance cannot take
place. People with APECED usually experience several autoimmune diseases simultaneously.
• Genetic polymorphisms affect how self peptides are expressed in the thymus. For example, insulin is
expressed in the normal thymus, where it tolerizes T cells through negative selection (Central tolerance). The
level of insulin expression in the thymus is genetically determined.
• Genetic polymorphisms may also affect peripheral tolerance. For example, hidden (“cryptic”) antigens may
become exposed to the immune system

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Environmental Factors and Loss of Tolerance

 Environmental factors, such as

infections, toxins, and stress, can
trigger or exacerbate autoimmune
reactions by modulating the immune
system's response to self-antigens.
 In some individuals, environmental
factors such as exposure to medications
and ultraviolet light trigger
autoimmunity. However, much more
commonly infection acts as an
environmental factor in breaking down
tolerance.
 Peripheral tolerance can break down:
 if tissue cells such as monocytes and
macrophages acquire the ability to
present self peptides.
 if molecular mimicry happens: an immune response to an infection elicits antibodies or T cells that cross-
react with host tissues. An example of this is acute rheumatic fever, which can occur rarely following
infection with the bacterium β-hemolytic Streptococcus.
 Finally, it is also possible that at crucial times, absence of infection can trigger autoimmunity! “This is the
hygiene hypothesis”
 If a particular strain of mice is kept in microorganism-free conditions, it will develop T1DM. If these mice are
exposed to everyday microorganisms, however, they are protected from diabetes. This observation has led
to the idea that reduced exposure to microorganisms may be responsible for the increase in prevalence of
autoimmune disease in developed countries.

The tests for autoimmune disease rely on detecting evidence of autoantibodies

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Type 1 diabetes (T1DM)

 Patient Presentation: Polyuria, Polydipsia, Polyphagia

 These symptoms are indicative of high blood sugar levels, which can occur in both type 1 and type 2
diabetes. It's essential for the patient to seek medical attention for proper diagnosis and management of
their condition. .
 Initial Tests: His fasting glucose levels were moderately elevated, but no ketones were found in his urine,
which isn't diagnostic of diabetes.
 Indirect immunofluorescence tests revealed the presence of islet cell antibodies in his serum. This finding
strongly suggested T1DM.
 T1DM is characterized by the destruction of insulin-secreting β-cells in the pancreatic islets by T cells. Islet
cell antibodies serve as markers of this autoimmune process but do not induce islet cell damage.
 T1DM is classified as a type IV hypersensitivity reaction. Autoreactive T cells invade the pancreatic islets,
leading to the destruction of β-cells. Regenerating β-cells after destruction is challenging, necessitating
lifelong insulin replacement.
 Genetic Factors: Genetic predisposition plays a significant role in T1DM. The human leukocyte antigen (HLA)
type, particularly the HLA-DQ alleles, confers about
90% of the genetic risk. Specific amino acid residue
changes at position 57 in HLA-DQ2 affect the risk for
developing T1DM.
 Environmental Factors: While genetics is crucial,
environmental factors, such as infections, are believed
to be important triggers. Viral infections, especially
coxsackievirus, have been suggested as possible
triggers, although no single infection consistently acts
as a trigger.
 Hygiene Hypothesis: Some researchers propose that
the absence of certain infections at specific ages may
trigger T1DM. This idea aligns with the hygiene
hypothesis, which suggests that reduced exposure to
microorganisms in early life may increase the risk of
autoimmune diseases.
 Prevention and Treatment: Screening siblings of
affected children for islet cell antibodies is possible.
Immunosuppressive drugs like cyclosporine can delay
the onset of diabetes temporarily. Research on
preventing T1DM is ongoing, including potential
vaccine strategies if specific triggering infections are
identified.

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Celiac Disease

 Celiac Disease: Celiac disease is the most common cause of small bowel disease in the developed world,
causing a range of clinical problems from mild anemia to severe malnutrition. It is an autoimmune disease
characterized by lymphocyte and macrophage infiltration of the jejunum, representing a type IV delayed
hypersensitivity reaction.
 Triggers: Celiac disease is triggered by two key antigens:
 Gliadin: Found in wheat, rye, and barley.
 tTG (Tissue Transglutaminase): An enzyme that modifies glutamine to glutamic acid and can bind to
substrate peptides.
 Patient Presentation: diarrhea and weight loss, indicating gastrointestinal issues.
 Genetic Factors: Identical twins have a high concordance rate (75%) for celiac disease. Most patients with
celiac disease inherit the HLA-DQ2 allele, which increases the risk of the disease. HLA genes are inherited as
haplotypes, and certain combinations of HLA alleles contribute to the occurrence of organ-specific
autoimmune diseases within families.

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Celiac Disease

 Diagnostic Tests: Blood tests reveal the presence of immunoglobulin A (IgA) autoantibodies against
endomysium and antibodies against tissue transglutaminase (tTG). These tests are considered diagnostic of
celiac disease in a child of this age.
 Treatment: The patient is started on a gluten-free diet, leading to a dramatic improvement in symptoms,
and the endomysial antibodies disappear after 6 months.
 Association with Other Diseases: Family members with celiac disease and type 1 diabetes mellitus (T1DM)
often develop other organ-specific autoimmune diseases like thyroid or adrenal disease and gastritis. These
diseases can coexist in the same individuals and are referred to as organ-specific autoimmune diseases.
 Haplotype Inheritance: HLA genes are closely situated on chromosome 6 and are often inherited as a block,
called a haplotype. One common haplotype includes HLA alleles B8, DR3, and DQ2, which is associated with
the development of organ-specific autoimmune diseases within families.
 Environmental Triggers: Different family members may develop different autoimmune diseases due to
slightly different environmental factors triggering each disease.

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SLE

 Patient Presentation: A young woman presents with a rash on sun-exposed areas of her face and painful
lesions on her toe pulps.
 SLE is an autoimmune disease mediated by immune complexes, specifically a type III hypersensitivity
reaction. The disease involves antibodies against DNA and other nuclear components.
 T-Cell Tolerance Loss: The key step in SLE's pathogenesis is the loss of T-cell tolerance to DNA.
 Genetic Factors: Genes play a significant role in SLE's development. The concordance rate for SLE in identical
twins is approximately 60%. Inheritance of the HLA allele DR2 and polymorphisms in genes related to debris-
clearing proteins increase the risk of SLE.
 Innate Immune System: Proteins of the innate immune system, such as mannan-binding lectin (MBL) and
complement component C1q, play a role in clearing cellular debris, including DNA fragments released during
cell death. Low levels of C1q or MBL increase the risk of SLE.
 Drug-Induced SLE: Some drugs, like hydralazine and procainamide, can induce SLE, possibly by inhibiting
methyltransferase enzymes involved in DNA clearance.

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 TLR-9 and IFN Production: Toll-like receptor 9 (TLR-9) on B cells and dendritic cells plays a role in recognizing
DNA motifs. In patients with SLE, immune complexes containing DNA can stimulate TLR-9, leading to
increased secretion of type 1 interferons (IFNs) and the production of anti-DNA antibodies.
 Gender and Estrogen: SLE is more common in women and is believed to be influenced by higher levels of
estrogen. Estrogen can increase antibody production, potentially contributing to autoantibody secretion in
SLE.
 UV Light Exposure: Exposure to ultraviolet (UV) light, particularly in sun-exposed areas, can trigger SLE
symptoms, including a characteristic rash. The exact mechanisms behind UV light's effects in SLE are not fully
understood but may involve apoptosis induction, proinflammatory cytokines, or tissue damage.
 Triggers: SLE may be triggered by factors like infections, UV light exposure, and estrogen. These factors can
switch patients from being symptom-free to experiencing symptomatic SLE.

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The End of immunology #23

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