Download Pathomechanism in RA-time for string theory?

Pathomechanism in RATime 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
cells
Polyclonal B cell activation
The production of autoantibodies such as RF,
The localization of immune complexes to the joint
1980s---1990s: changed to T cells
Association of particular MHC alleles:HLA-DR4
CD4+ T cells may be important in the initiation and
progression of RA-associated joint disease
Macrophage/DC: IL-1, IL-6, TNF-a in joint/anti-TNF-a Tx
Revival of the Autoantibody Model
in Rheumatoid Arthritis
溫故 知新
Toshino Hirano
Nat Immunol 2002 April
《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 RA
Strain 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
KBN mouse model
TNF-a
TNF-a Independent
pathway
Autoreactive T-B cell interaction
CD40L-CD40
Arthritogenic autoantibody
Environmental
epigenetic
IL-1
C5a/FcgRIII
Process of Synovial pathology
Deposit in the joint
1hr
Mast cell granule
degranulation
Destructive Arthritis
24hr
48hr
Neutrophil
recruitment
72hr
Months--years
Synovial
T cell
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
observed CCP reactivity?
Whether it is direct pathogenic or not, what effect is
it ?
If it is modifier, Can it is induced tolerance?
Anti-CCP antibodies appear prior to visible arthritis and in
parallel with the appearance of anti-collagen antibodies
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
A population of antibodies in CIA is specific for the citrullinated
proteins filaggrin and fibrinogen
A: RA patient
B: CIA 35days aft imm
C: Adjuvant control
D: Untreated
E: Preabsorpted CPP(LXP)
F: LRP(control)
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
Antibodies specific to citrullinated fibrinogen substantially
enhance submaximal arthritis
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
Antibodies specific to citrullinated fibrinogen substantially
enhance submaximal arthritis
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
D513, 1042, and 1618 monoclonal antibodies bind antigens
within the inflamed synovium of mice with CIA
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
Mice tolerized with a citrullinated peptide are significantly
protected from CIA
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
Antibodies against citrullinated fibrinogen can overcome the
protective effect of tolerance to citrullinated antigens
Kuhn, K. A. et al. J. Clin. Invest. 2006;116:961-973
Copyright ©2006 American Society for Clinical Investigation
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.
The complexities of RA
Weyand, C. M. et al. J. Clin. Invest. 2006;116:869-871
Copyright ©2006 American Society for Clinical Investigation
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
open strings
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
String Theory
만물의 최소 단위가 점 입자가 아니라 '진동하는 끈'으로 이루
어져 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 4가지의 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 Theory
끈이론을 연구하는 물리학자들은 자연계에 존재하는 이 4가지
힘과 모든 물질을 하나의 원리로 통합할 수 있다고 주장하고 있
다.
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 시
작했다. 그리고 끈의 진동 형태에 따라 입자의 질량을 비롯한 모
든 물리적 성질들이 결정되고 우주도 이에 따라 형성된다는 것
이다.
String Theory
곧, 끈의 진동이 격렬하면 에너지가 많다는 뜻이며, 거기에 대
응해 질량의 무게도 커진다. 반대로 끈의 진동이 약하면 에너
지가 작다는 것이고, 거기에 대응해 질량의 무게 역시 작아진
다. 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 50년 동안 과학계를 지배했던 빅뱅이
론을 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 jungleA 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.