T cells in Autoimmunity: studies on murine type II collagen-induced arthritis

Alexandre Corthay

T cells in Autoimmunity: studies on murine type II collagen-induced arthritis

Alexandre Corthay

Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

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Popular Abstract in Swedish
Kan immunförsvaret orsaka ledsjukdomar?

Ett väl fungerande immunsystem är en förutsättning för att kroppen ska kunna bekämpa diverse sjukdomar orsakade av t. ex. virus och bakterier. En grundläggande egenskap hos immunsystemet är dess förmåga att kunna skilja på vad som är kroppens egna celler och molekyler och vad som är främmande. Man tror att vissa sjukdomar, så kallade autoimmuna sjukdomar, beror på att immunförsvaret av misstag attackerar kroppens egna celler och vävnader som då förstörs. Ledgångsreumatism, eller reumatoid artrit (RA), misstänks vara en sådan autoimmun sjukdom. RA drabbar cirka 1 % av västvärldens befolkning och är vanligare hos kvinnor än hos män. Sjukdomen kännetecknas av kronisk inflammation i lederna, som leder till att ben och brosk bryts ner och så småningom att lederna deformeras. Orsaken till RA är fortfarande okänd, men man tror att sjukdomen beror på att immunförsvaret angriper lederna.

För att kunna studera hur immunsystemet kan orsaka en sjukdom, använder vi oss av djurmodeller för RA. En sådan modell är kollagen inducerad artrit (CIA) där vi framkallar artrit genom att injicera möss med kollagen typ II, ett protein som bara finns i brosk. I denna modell har vi studerat T celler, som är en viss typ vita blodkroppar. T cellernas huvudfunktion i immunförsvaret är att dirigera resten av immuncellerna och tala om när och var det är dags att angripa inkräktare.

I CIA modellen har vi kunnat visa att möss som saknar T celler på grund av en gendefekt, aldrig utvecklar artrit. Det tyder på att T celler och därmed immunsystemet spelar en huvudroll i artrit. När vi närmare undersökte rollen för T celler i CIA, visade det sig att vissa T celler kan specifikt känna igen typ II kollagen. Dessa T celler reagerar mot en liten del av kollagen som innehåller en socker molekyl. Våra resultat visar sammanfattningsvis att T cellerna i immunsystemet spelar en nyckelroll i artrit utvecklingen och vi har kunnat identifiera hur T cellerna känner igen brosk kollagenet.

Originalspråk	engelska
Kvalifikation	Doktor
Tilldelande institution
Handledare	[unknown], [unknown], handledare, Extern person
Tilldelningsdatum	2000 mars 10
Förlag	Lund University, Section for Medical Inflammation Research, Sölvegatan 19, SE-223 62 Lund, Sweden
ISBN (tryckt)	91-628-4037-1
Status	Published - 2000

Bibliografisk information

Defence details

Date: 2000-03-10
Time: 13:00
Place: Rune Grubb Salen, BMC, Sölvegatan 19, Lund, Sweden

External reviewer(s)

Name: Kollias, George
Title: Professor
Affiliation: Hellenic Pasteur Institute, Athens, Greece

---

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Medical Inflammation Research (013212019)

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Immunologi inom det medicinska området

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title = "T cells in Autoimmunity: studies on murine type II collagen-induced arthritis",

abstract = "Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis, in which autoimmunity is induced by immunization with type II collagen (CII), a cartilage-specific protein. In the present work, alpha/beta T cells were shown to be required for CIA and for the production of anti-CII IgG antibodies, whereas gamma/delta T cells were neither necessary nor sufficient for development of CIA. Approximately 8% of total peripheral T cells in normal mice were found to express two distinct T cell receptor (TCR) alpha chains at the surface, revealing a lack of phenotypic allelic exclusion in TCR alpha. However, the presence of such a high numbers of potentially multireactive T cells did not increase susceptibility to CIA. We also investigated the occurance of spontaneous arthritis in male DBA/1 mice, the most frequently used strain for CIA, and revealed that it is an alpha/beta T cell-independent enthesopathy that was histologically very different from CIA. Finally, we determined the T cell epitopes on CII, and the TCR structures used for their recognition. Posttranslational modifications (hydroxylation and variable glycosylation) of a single lysine at position 264 of CII were shown to generate four distinct T cell determinants that were specifically recognized by distinct T cell subsets with distinct TCR repertoires. Most T cells, after immunization with CII, recognized CII(256-270) glycosylated with a monosaccharide. The observation that the immunodominant T cell determinant in CIA is a glycopeptide, suggests that induction of self-tolerance may be rendered more difficult by posttranslational glycosylations of proteins. Under special circumstances, like trauma, inflammation or aging, creation of new self epitopes by posttranslational modifications may trigger an autoimmune attack.",

keywords = "Immunologi, Autoimmunity / T lymphocytes / collagen-induced arthritis / Glycosylation / TCR, transplantation, serology, Immunology, serologi, Skeleton, muscle system, rheumatology locomotion, Skelett, muskelsystem, reumatologi",

author = "Alexandre Corthay",

note = "Defence details Date: 2000-03-10 Time: 13:00 Place: Rune Grubb Salen, BMC, S{\"o}lvegatan 19, Lund, Sweden External reviewer(s) Name: Kollias, George Title: Professor Affiliation: Hellenic Pasteur Institute, Athens, Greece --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)",

year = "2000",

language = "English",

isbn = "91-628-4037-1",

publisher = "Lund University, Section for Medical Inflammation Research, S{\"o}lvegatan 19, SE-223 62 Lund, Sweden",

type = "Doctoral Thesis (compilation)",

}

TY - THES

T1 - T cells in Autoimmunity: studies on murine type II collagen-induced arthritis

AU - Corthay, Alexandre

N1 - Defence details Date: 2000-03-10 Time: 13:00 Place: Rune Grubb Salen, BMC, Sölvegatan 19, Lund, Sweden External reviewer(s) Name: Kollias, George Title: Professor Affiliation: Hellenic Pasteur Institute, Athens, Greece --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)

PY - 2000

Y1 - 2000

N2 - Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis, in which autoimmunity is induced by immunization with type II collagen (CII), a cartilage-specific protein. In the present work, alpha/beta T cells were shown to be required for CIA and for the production of anti-CII IgG antibodies, whereas gamma/delta T cells were neither necessary nor sufficient for development of CIA. Approximately 8% of total peripheral T cells in normal mice were found to express two distinct T cell receptor (TCR) alpha chains at the surface, revealing a lack of phenotypic allelic exclusion in TCR alpha. However, the presence of such a high numbers of potentially multireactive T cells did not increase susceptibility to CIA. We also investigated the occurance of spontaneous arthritis in male DBA/1 mice, the most frequently used strain for CIA, and revealed that it is an alpha/beta T cell-independent enthesopathy that was histologically very different from CIA. Finally, we determined the T cell epitopes on CII, and the TCR structures used for their recognition. Posttranslational modifications (hydroxylation and variable glycosylation) of a single lysine at position 264 of CII were shown to generate four distinct T cell determinants that were specifically recognized by distinct T cell subsets with distinct TCR repertoires. Most T cells, after immunization with CII, recognized CII(256-270) glycosylated with a monosaccharide. The observation that the immunodominant T cell determinant in CIA is a glycopeptide, suggests that induction of self-tolerance may be rendered more difficult by posttranslational glycosylations of proteins. Under special circumstances, like trauma, inflammation or aging, creation of new self epitopes by posttranslational modifications may trigger an autoimmune attack.

AB - Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis, in which autoimmunity is induced by immunization with type II collagen (CII), a cartilage-specific protein. In the present work, alpha/beta T cells were shown to be required for CIA and for the production of anti-CII IgG antibodies, whereas gamma/delta T cells were neither necessary nor sufficient for development of CIA. Approximately 8% of total peripheral T cells in normal mice were found to express two distinct T cell receptor (TCR) alpha chains at the surface, revealing a lack of phenotypic allelic exclusion in TCR alpha. However, the presence of such a high numbers of potentially multireactive T cells did not increase susceptibility to CIA. We also investigated the occurance of spontaneous arthritis in male DBA/1 mice, the most frequently used strain for CIA, and revealed that it is an alpha/beta T cell-independent enthesopathy that was histologically very different from CIA. Finally, we determined the T cell epitopes on CII, and the TCR structures used for their recognition. Posttranslational modifications (hydroxylation and variable glycosylation) of a single lysine at position 264 of CII were shown to generate four distinct T cell determinants that were specifically recognized by distinct T cell subsets with distinct TCR repertoires. Most T cells, after immunization with CII, recognized CII(256-270) glycosylated with a monosaccharide. The observation that the immunodominant T cell determinant in CIA is a glycopeptide, suggests that induction of self-tolerance may be rendered more difficult by posttranslational glycosylations of proteins. Under special circumstances, like trauma, inflammation or aging, creation of new self epitopes by posttranslational modifications may trigger an autoimmune attack.

KW - Immunologi

KW - Autoimmunity / T lymphocytes / collagen-induced arthritis / Glycosylation / TCR

KW - transplantation

KW - serology

KW - Immunology

KW - serologi

KW - Skeleton

KW - muscle system

KW - rheumatology locomotion

KW - Skelett

KW - muskelsystem

KW - reumatologi

M3 - Doctoral Thesis (compilation)

SN - 91-628-4037-1

PB - Lund University, Section for Medical Inflammation Research, Sölvegatan 19, SE-223 62 Lund, Sweden

ER -

T cells in Autoimmunity: studies on murine type II collagen-induced arthritis

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