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Autoimmune Disease: When the immune system acts in response to self-antigens and causes damage to one’s own organs

Autoimmunity might happen on a small scale, but once it crosses a threshold it turns into an autoimmune disease.

Celiac disease is not an autoimmune disease because it is not responding to an antigen coming from the body but one coming from gluten.

Celiac Disease and Allergies use different T-Cells
> Allergies - TH2
> Celiac TH1 & TH17

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B Cells
> White blood cells that make antibodies

Antibodies
> a blood protein produced in response to counteract a specific antigen

T Cells
>  T cells circulate until they encounter a foreign antigen

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Paneth Cells
Paneth cells are located in the Villi and help break down fatty acids to absorb nutrients.
> They secrete antimicrobial peptides that kill pathogens in the membrane.
> They have an important role in the immune system
> Interaction with the migration and replacement of villi
> Stress, genetic predisposition make the membrane more permeable

Innate Immunity

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Autoinflammatory/Autoimmune disease in response to gluten ingestion in people who are genetically predisposed.

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There is inflammation, failure to thrive, and abdominal pain.
Lowers life expectancy when detected after 18 years old
Can progress into lymphoma & osteoporosis

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Genetic Predisposition to Celiac Disease 

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Genetic Predisposition to Celiac Disease 

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HLA-DQ
> (HLA-)DQ2 or (HLA-)DQ8 alleles predispose a person to celiac disease
> Homozogous (two copies) DQ2 is possessed by most people with Celiac disease
> DQ8 still causes a risk for Celiac disease
> Possible Exam Question: Which combination between DQ2 & DQ8 will result in Celiac disease?

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IgA antibodies

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Role of Gluten and the Role of the Immune System in the Pathology of Celiac Disease 

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Role of Gluten and the Role of the Immune System in the Pathology of Celiac Disease 

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a) Sequence of Events

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Explain the role of the adaptive immune system in celiac disease 

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Explain the role of the adaptive immune system in celiac disease 

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https://pathology.jhu.edu/autoimmune/definitions

https://www-nature-com.eur.idm.oclc.org/articles/s41572-018-0054-z.pdf

The Immune System Book

Article: “Triggers and drivers of autoimmunity: lessons from coeliac disease” by Ludvig M. Sollid and Bana Jabri

Youtube: https://www.youtube.com/watch?v=Hxd0msD954I&ab_channel=ArmandoHasudungan

Hypersensitivity: Microbiology: An Introduction - Chapter 19 (Pg 551-568)

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An antigenic response that results in undesirable effects in a damaging manner.
> Caused by a particular antigen
- Type I - response within 30 minutes
> Allergies
- Type II - cytotoxic, response in 5 to 12 hours

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THE PREVALENCE OF HLA DQ2 AND DQ8 IN PATIENTS WITH CELIAC DISEASE, IN FAMILY AND IN GENERAL POPULATION

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THE PREVALENCE OF HLA DQ2 AND DQ8 IN PATIENTS WITH CELIAC DISEASE, IN FAMILY AND IN GENERAL POPULATION

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737358/pdf/0102-6720-abcd-28-03-00183.pdf

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Gluten is broken down, releasing gliadin.

Gliadin is first broken down by amylase in the mouth, once in the lumen it is broken down into smaller peptides that allow it to cross the lamina propia.

Passage to the lamina propia by compromised epithelial complex damaged by stress, bacterial toxin, or genetic predisposition.

In the lamina propia, gliadin peptides are modified by transglutaminase 2 (TG2) which deamidates the glutamine residues into glutamic acid

Increasing their affinity for HLA-DQ2 or HLA-DQ8 due to their more negative charge

Tight junctions proteins are released

Macrophages & dendritic cells absorb the deamidated molecule and present the gliadin peptide in the HLA.

CD4+T-cells bind to the antigens presented by the dendritic cell.

TH1 reaction --> proliferation and production of cytokines (inflammation)

TH2 reaction --> Activation and stimulates B cells to create antibodies IgA ( found in secretion), IgG (detoxifies, and recognition of antibodies complexes), IgM

Different antibodies: one against gluten, one against TG2

IgA attacks gliadin, TG2, and endomysial antibodies

Activated B cells can differentiate into plasma cells that secrete antibodies against Gluten and TG2

Intraepithelial lymphocytes are found in the GI and reproductive tract

Contribute to the damage (villous atrophy) and are a marker for the disease

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Adaptive immune responses involved in coeliac disease. Owing to a high proline content, gluten is fairly resistant to proteolytic degradation by mammalian
and microbial digestive enzymes, which leads to the appearance of fairly long gliadin peptides, including the 33mer, in the small intestinal lumen. These peptides access
the lamina propria either actively through the transepithelial route or passively by paracellular flux caused by compromised epithelial barrier function. In the lamina propria, the immunogenic gliadin peptides are modified by transglutaminase 2 (TG2), which deamidates distinct glutamine residues into glutamic acid, increasing their affinity to human leukocyte antigen (HLA)-DQ2 or HLA-DQ8. These modified epitopes are taken up by antigen-presenting cells, including dendritic cells that present them to gluten-specific CD4+ T cells in the context of HLA-DQ2 or HLA-DQ8 molecules. Moreover, both gluten-specific and TG2-specific B cells have been suggested to act as antigen-presenting cells in coeliac disease. B cells recognize their antigens (gliadin peptides and TG2–gliadin complexes) via surface B cell receptors (BCRs), internalize them and present the processed gluten peptides to gluten-specific CD4+ cells. Upon the interaction of HLA-DQ2 or HLA-DQ8, gliadin peptides and distinct T cell receptors (TCRs), both the T cells and the B cells would be activated. Once activated, gluten- specific CD4+ T cells start secreting inflammatory cytokines, including IFNγ and IL-21, thereby creating an inflammatory milieu in the small intestinal lamina propria. Moreover, the activated B cells can differentiate into plasma cells that secrete antibodies against gluten and TG2. IEL, intraepithelial lymphocyte.

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HLA class in patients with celiac disease

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HLA class in patients with celiac disease

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https://reader.elsevier.com/reader/sd/pii/S1074761304002390?token=9D201D7553CBC90D228F40E08F7D5A4979A430FDA0066DD71C9B0EA525034085054272A1F258F45436020445DCDEB418&originRegion=eu-west-1&originCreation=20220421111124

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003135/pdf/cmi201065a.pdf

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Infants exposed to dietary gluten early and in the presence of maternal IgA become tolerant of gluten, whereas infants exposed later and in the absence of maternal IgA are more likely to respond to gluten as though it were an infecting pathogen

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Gluten-free diet
> 30% of the patients do not respond to this treatment
--> Immunosuppressant to reduce inflammation
Take vitamin A, K, D, B12, Selenium
Don't take supplements unless you need them

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Pathogenesis of celiac disease
Ingestion
• Gluten-containing grains (wheat, barley, rye) are ingested
Entering digestive system
• The protein “gluten” enters into the digestive system
Intestinal proteases
Gluten is degraded in the gut lumen to resistant fragment (proline-rich 33-residue gliadin
fragment).
• Gluten consists of proline- and glutamine-rich gliadin and glutenin subcomponents and the
glutamine and proline-rich gluten composing proteins are partially hydrolyzed by proteases
presented in the gastrointestinal.
• The high content of proline in gluten proteins makes them resistant to degradation by
intestinal proteases such that they can be found as long fragments (10–50 residues) in the gut
lumen.
• The proline-rich 33-residue gliadin fragment resists proteolysis, both by the extracellular
digestive enzymes and the intracellular proteases of antigen processing
Substrate transglutaminase
• These gluten fragments are good substrates for the enzyme transglutaminase, which converts
certain glutamine residues to glutamate.
• The proline-rich 33-residue gliadin fragment binds strongly to tissue transglutaminase.
Deamination
• Resistant fragment enters gut tissue and is deaminated by transglutaminase.
• This process, known as deamidation, increases the ability of the gluten peptides to bind to
HLA-DQ2 or HLA-DQ8 molecules.
• After transglutaminase has converted particular glutamine residues to glutamate, the 33-
residue fragment binds to HLA-DQ
Activation inflammatory effector T cells
• By binding to HLA-DQ in different registers, the fragment presents distinctive epitopes to
different clones of T cells; these have a synergistic effect in initiating the disease-causing
immune response.
• Naïve CD4 T cell responds to deaminated peptides presented by HLA (HLA-DQ, DQ2 or DQ8
allotypes).
• CD4 TH1 cells that respond to gluten-derived peptides presented by DQ2 or DQ8 allotypes
and secrete cytokines that orchestrate the inflammatory response.
Inflammatory response
• Inflammatory effector T cells secrete cytokines that orchestrate the inflammatory response.
• Inflammatory effector T cells cause villous atrophy.

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The disease is characterized by the presence of specific serological antibodies, such as: anti-
tissue transglutaminase (tTG) IgA, anti-endomysium IgA (EMA) and anti-deamidated gliadin
peptides IgG (DPG).
All patients with celiac disease make IgG or IgA autoantibodies specific for tissue
transglutaminase. The presence of such antibodies is diagnostic for the disease, which is
confirmed by biopsy of the small intestine. HLA-DQ typing can also be informative in
diagnosis, because patients who lack DQ2 or DQ8 do not have celiac disease but have some
other intestinal disorder. Most celiacs also make anti-gliadin antibodies. These antibodies are
likely to be the products of B cells expressing surface immunoglobulins that bind and
internalize complexes of transglutaminase and a gliadin fragment and then present modified
gliadin fragments on HLA-DQ molecules to T cells.
Tissue transglutaminase (tTG)
Generated gluten-derived peptides reach the lamina propria (mucosa) where they are
modified by tTG enhancing their affinity to MHC II molecules, and thereby making them toxic
and immunogenic in HLA-DQ2 or DQ8 containing patients. The repetitive presence of
glutamine and proline residues determines the gluten-derived peptides as a preferred
substrate for tTG. tTG-mediated modifications occur in two ways: deamidation (cleavage of
the ε-amino group of a glutamine side chain) or more frequently transamidation (cross-
linking of a glutamine residue from the gliadin peptide to a lysine residue of tTG). Further
peptides presentation by HLA-DQ2/DQ8 protein subunits in the surface of dendritic cells to
gluten-specific T cells induces two levels of immune response: the innate response and the
adaptive (T-helper cell mediated) response with the production of interferon-γ and IL-15. As
a result, it causes immune-mediated enteropathy, intestinal inflammation, followed by the
atrophy of villi, crypt hyperplasia and increased infiltration by intraepithelial lymphocytes. It
also produces weight loss and chronic diarrhea. Although the causative agent is a dietary
protein, the disease has marked autoimmune features, which are indicated by the presence
of autoantibodies against tTG. Cross-linking between gliadin and tTG is covalent resulting in
the formation of new epitopes, which trigger the primary immune response, and by which
the autoantibodies against tTG are developed.