pathomechanism in ra- time for string theory? 원장 정 성 수
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Pathomechanism in RA-Time for string theory?
원장 정 성 수
Paradigm Shift of principal effectors in RA :The New Idea resides within the old
1970s: B cells and their products were the preferred candidate effector cellsPolyclonal B cell activationThe production of autoantibodies such as RF,The localization of immune complexes to the joint
1980s---1990s: changed to T cellsAssociation of particular MHC alleles:HLA-DR4CD4+ T cells may be important in the initiation and pro
gression of RA-associated joint diseaseMacrophage/DC: IL-1, IL-6, TNF- in joint/anti-TNF- Tx
Revival of the Autoantibody Model in Rheumatoid Arthritis
Toshino HiranoNat Immunol 2002 April
溫故 知新
《논어 ( 論語 ) 》 < 위정편 ( 爲政篇 )> 에 나오는 공자의 말 중에 “옛 것을 알고 새 것을 알면 남의 스승이 될 수 있다 ( 溫故而知新可以爲師矣 ).”
A New Model for Human RAStrain K/BxN ; KRN x C57BL/6 TCR transgenic line x NOD Kouskoff, V.Korganow, A. S.Duchatelle, V.Degott, C.Benoist, C.Mathis, D.: Organ-specific disease provoked by systemic autoimmunity. Cell 1996.
• KRN TCR normaly recognizes a bovine ribonuclease peptide presented by the MHC class II molecule I-Ak
• In the context of the NOD-derived I-Ag7 MHC class II molecule, KRN TCR recognizes a second peptide derived from a ubiquitouly expressed protein. • The molecule recognized by the KRN TCR in the context of I-Ag7 and the arthritogenic Ig was identified as glucose-6-phosphate isomerase(GPI): Matsumoto, I.Staub, A.Benoist, C.Mathis, D.: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 1999• In human, 64% of the people with RA that were tested had increased concentrations of the anti-GPI IgG in their serum/SF.:Schaller, M.Burton, D. R.Ditzel, H. J.: Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease. Nat Immunol 2001
Time kinetics of Inflammatory arthritis
Arthritogenic autoantibody
1hr 24hr 48hrMast cell granule degranulation
Neutrophil recruitment
Autoreactive T-B cell interaction
Deposit in the joint
Process of Synovial pathology
72hr
CD40L-CD40
TNF-
IL-1
Destructive Arthritis
C5a/FcRIII
TNF-Independentpathway
Environmental epigenetic
Months--yearsSynovialT cell
KBN mouse model
Antibodies against citrullinated proteins
APF, AKA-bind a specific protein, filaggrin, found within keratohyalin granules and cornified epithelium.
Citrulline Residue-filaggrin is produced in the late stages of terminal differentiation of epithelial cells during keratinization.The precursor profilaggrin is produced and stored in granules until terminal differentiation.At this point, profilaggrin is proteolytically cleaved and dephosphorylated, and certain arginine residues are deiminated by specific peptidyl arginine deiminases(PADs) to form citrulline residue.
Sensitivity :68% Specificity:98%
• Nielen, M. M.: Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. 2004 Arthritis Rheum
• Rantapaa-Dahlqvist, S.: Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. 2003 Arthritis Rheum
Key words: Rheumatoid arthritis & citrullinated peptide
Rheumatoid arthritis & Anti-CCP
• Disease severity or aggressiveness
• Response predictor to therapy
• Relevance to pathogenesis of RA
Questions
Are there CCP in this model? If so , where ?Whether is anti-CCP in this model ?If so, When does anti-CCP appear in disease course?Is it specific to the citrulline modification in observe
d CCP reactivity?Whether it is direct pathogenic or not, what effect is
it ?If it is modifier, Can it is induced tolerance?
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Anti-CCP antibodies appear prior to visible arthritis and in parallel with the appearance of anti-collagen antibodies
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
A population of antibodies in CIA is specific for the citrullinated proteins filaggrin and fibrinogen
A: RA patientB: CIA 35days aft immC: Adjuvant controlD: UntreatedE: Preabsorpted CPP(LXP)F: LRP(control)
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Antibodies specific to citrullinated fibrinogen substantially enhance submaximal arthritis
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Antibodies specific to citrullinated fibrinogen substantially enhance submaximal arthritis
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
D513, 1042, and 1618 monoclonal antibodies bind antigens within the inflamed synovium of mice with CIA
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Mice tolerized with a citrullinated peptide are significantly protected from CIA
Copyright ©2006 American Society for Clinical Investigation
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Antibodies against citrullinated fibrinogen can overcome the protective effect of tolerance to citrullinated antigens
Conclusion
• Infiltrating neutrophil released PAD into extracellular matrix during apoptosis
• As fibrin is a common constituent of the inflamed synovium, it may serve as a local substrate for PAD, generating citrullinated antigens in situ.
Copyright ©2006 American Society for Clinical Investigation
Weyand, C. M. et al. J. Clin. Invest. 2006;116:869-871
The complexities of RA
What is String Theory? String theory describes a physical model of the universe in which the fundamental building blocks are not point particles, but rather one-dimensional "strings". According to this model, every fundamental particle exists as a different vibration mode of the string, where each vibration has different associated properties.
open strings
closed strings
open strings
String Theory만물의 최소 단위가 점 입자가 아니라 ' 진동하는 끈 ' 으로 이루어져 있다는 이론 .
그 끈은 우리가 흔히 알고 있는 원자와 분자로 이루어져 있는 끈이 아니라 더 이상의 세부구조를 갖고 있지 않는 가장 기본 단위( 쿼크 ) 를 말한다 .
자연계에는 4 가지의 힘이 존재하는데 , I. 뉴턴 (Isaac Newton)의 만유인력을 설명하는 중력과 J. C. 맥스웰(James Clerk Maxwell) 의 전자기 법칙을 설명하는 전자기력, 물질의 붕괴를 설명하는 약력 그리고 핵의 구조를 설명하는 강력이 그것이다 .
String Theory끈이론을 연구하는 물리학자들은 자연계에 존재하는 이 4 가지 힘과 모든 물질을 하나의 원리로 통합할 수 있다고 주장하고 있다 .모든 입자의 원자내 구조를 설명해 주는 끈이론은 , 자연계의 기본입자가 하나의 자유도를 갖는 점 (point) 이 아니라 무한한 자유도를 갖는 1차원 끈 (string) 으로 되어 있다는 가설에서 시작했다 . 그리고 끈의 진동 형태에 따라 입자의 질량을 비롯한 모든 물리적 성질들이 결정되고 우주도 이에 따라 형성된다는 것이다 .
String Theory곧 , 끈의 진동이 격렬하면 에너지가 많다는 뜻이며 , 거기에 대응해 질량의 무게도 커진다 . 반대로 끈의 진동이 약하면 에너지가 작다는 것이고 , 거기에 대응해 질량의 무게 역시 작아진다 . 이것은 끈의 진동세기에 의해 힘의 크기가 결정되고 , 끈의 진동패턴 ( 모양 ) 의 변화에 따라 힘의 종류 ( 중력 , 전자기력 , 약력 , 강력 ) 가 결정된다는 것을 의미한다 .
이로써 끈이론은 일반상대성이론과 양자역학의 충돌이 되는 중력 문제를 해결하고 모든 것을 설명하는 통합이론으로서의 실마리를 제공하고 있다 . A. 아인슈타인의 일반상대성이론이 틀렸음을 지적하고 , 지난 50 년 동안 과학계를 지배했던 빅뱅이론을 부정하며 , 전혀 다른 개념의 우주론을 제시하는 혁명적인 이론이라 할 수 있다 .
We need to develop a new theory for this disease
We may want seek guidance from our colleagues in physics and mathematics who have successfully integrated their knowledge of elementary particles and the complexity of their interacting forces by formulating the string theory.
Bringing light to the jungle- A unified theory of
autoimmunity
How could we go about formulating a string theory of autoimmunity?
Big ideas, like a generalization of how the immune system fails and causes inflammatory destruction of tissues, come along rarely.
Considering the enormous progress that has been made in understanding what goes wrong in RA, the time may have come step out of the boundaries of current paradigms and work to formulate theories that are able to synthesize the complexities of autoimmune diseases.