Artritis ReumatoideFISIOPATOLOGAETIOLOGY AND PATHOGENESIS OF
RHEUMATOID ARTHRITISRheumatoid arthritis (RA) is a complex disease
involving numerous cell types, including macrophages, T cells, B
cells, fibroblasts, chondrocytes, and dendritic cells.Several genes
are implicated in susceptibility to RA and severity of disease,
including classma!or histocompatibility complex genes, "T"#$$ (
"rote%na &infoide Tirosina 'osfatasa (&)"* codificada por
el gen "T"#$$ + e!erce una potente inhibici,n en el linfocito T
activado), and peptidylarginine transferases.-vidence of
autoimmunity, including high serum levels of autoantibodies such as
rheumatoid factors and anticitrullinated peptide antibodies, can be
present for many years before the onset of clinical
arthritis.Adaptive and innate immune responses in the synovium have
been implicated in the pathogenesis of RA..yto/ine net0or/s
involving tumor necrosis factor, interleu/in*1, and many other
factors participate in disease perpetuation and can be targeted by
therapeutic agents.Bone and cartilage destruction seem to be
primarily mediated by osteoclasts ad !i"ro"last#li$e
s%o&ioc%tes'ETIOLOGY OF RHEUMATOID ARTHRITIS2enes play a /ey
role in susceptibility to RA and disease severity..lass34. genes,
especially genes containing a specific 5*amino acid se6uence in the
hypervariable region of 4&A*7R8, are the most prominent genetic
association.#e0ly defined genetic associations, including
polymorphisms in "T"#$$, "A7 8 ("eptidyl arginine deiminase, type
9), and many cyto/ines, suggest that the associations in RA are
complex and involve many genes.T(e )rimar% !uctio o! HLA#DR is to
)reset )e)tide ati*es+ )otetiall% !orei* i ori*i+ to t(e immue
s%stem for the purpose of eliciting or suppressing T*(helper)*cell
responses that eventually lead to the production of antibodies
against the same peptide antigen. Antigen presenting cells
(macrophages, B*cells and dendritic cells) are the cells in 0hich
7R are typically found. ncreased abundance of 7R :antigen: on the
cell surface is often in response to stimulation, and, therefore,
7R is also a mar/er for immune stimulation.POSSI,LE -AUSES OF
RHEUMATOID ARTHRITIS3any pathogens have been associated 0ith RA,
including viruses, retroviruses, and 3ycoplasma, although a precise
etiologic lin/ has not been established.7ata suggest that a
specific RA pathogen is unli/ely.Repeated inflammatory insults,
especially through speciali;ed receptors that recogni;e common
molecules produced by pathogens, in a genetically susceptible
individual might contribute to brea/do0n of tolerance and
subse6uent autoimmunity.T(e "rea$do. o! tolerace ad/or
immuore*ulator% mec(aisms leads to autoimmue acti&atio ad
reco*itio i t(e tissues. These responses, 0hich are :adaptative: in
their anti*self specificity, generate primary :innate: inputs into
mast cells, such as immune complex binding to 'cRs, and ., 23*.S',
and many others, can help perpetuate synovial
inflammation..hemo/ines that recruit inflammatory cells into the
!oint generally are produced by macrophages and
fibroblasts.Anti*inflammatory cyto/ines, such as &*?Ra and
&*?@, are produced in rheumatoid synovium, albeit in amounts
insufficient to offset proinflammatory cyto/ines..yto/ine net0or/s
in rheumatoid arthritis. "aracrine and autocrine path0ays can lead
to activation of fibroblast*li/e and macrophage*li/e synoviocytes
in the synovial intimal lining. "ositive (=) and negative (*)
feedbac/ loops are present, although in rheumatoid arthritis the
former predominate. T helper type ? (Th?) cyto/ines potentially can
enhance the net0or/, 0hereas Th$ cyto/ines are suppressive. '2',
fibroblast gro0th factorC 23*.S', granulocyte*macrophage
colony*stimulating factorC &, interleu/inC 3*.S', macrophage
colony*stimulating factorC T2', transforming gro0th factorC T#',
tumor necrosis factor. SIGNAL TRANSDU-TION AND TRANS-RIPTION
FA-TORS.omplex intracellular signaling mechanisms regulate cyto/ine
production and actions in RA synovium.#'LB, 3A" /inases (mitogen
activated protein) , A"*? (prote%na activadora ?, es un factor de
transcripci,n) , and several other path0ays are potential
therapeutic targets in RA.Intracellular signaling pathways
initiated at the CD4 T-cell receptor complex. The TCR and
coreceptor (in this example the CD4 molecule), associated signaling
molecules, their coupling to downstream iochemical e!ents and
culmination in nuclear gene transcriptionare shown. "pon
antigen#$%C ligand inding to the TCR and coreceptor, the proximal
&inases 'c& and (yn phosphorylate tyrosine residues on the
IT)$ regions in the intracytoplasmic domains o* CD+ and TCR,
recruiting ,)--./ to ind to phosphorylated tyrosine residues on the
TCR chains. The ound ,)--./ ecomes phosphorylated, acti!ating the
&inase to phosphorylate the adapter proteins ')T and 0'--.1,
which in turn leads to the acti!ation o* -'C- y Tec &inases and
the acti!ation o* Ras y guanine-nucleotide exchange *actors (23(s).
)cti!ated -'C- and Ras initiate three important pathways that
culminate in the acti!ation o* transcription *actors in the
nucleus. Together 4(5, 4()T, and )--6 act on the T-cell
chromosomes, initiating new gene transcription. ((rom %ocherg $,
0ilman ), 7einlatt $, et al. Rheumatology, 4th ed. 'ondon# $osy,
8//9, (ig. 68.8.)LIFE AND DEATH IN THE RHEUMATOID SYNO0IUMReactive
oxygen and nitrogen in RA !oints contributes to a toxic environment
that can damage cells and increase inflammation.7eficient
apoptosis, or cell death, can contribute to the accumulation of
cells in rheumatoid synovium.Abnormalities of /ey regulatory genes,
such as the p5< tumor*suppressor gene, can enhance accumulation
of cells in the !oint. nducing apoptosis potentially can suppress
synovial inflammation and !oint destruction."ost*translational
modification of apoptotic regulators constitute an important
mechanism by 0hich RA synovial fibroblasts are protected from
apoptosis. Specifically, increased expression of SM3F*? results in
an enhanced SM3Fylation of the nuclear "3& protein, as a result
of 0hich the apoptotic modulator 7ANN is bound at increased levels
in the "3& nuclear bodies. nhibition of SM3F*? (molOcula
pe6uePa modificadora tipo ubi6uitina*?) (SM3F*?) or overexpression
of the nuclear SM3F(specific protease S-#"? results in
deSM3Fylation of "3& and the release of 7ANN, resulting in
sensiti;ation of RA fibroblasts to programmed cell death. (Q SM3F ?
+ Q apoptosis),LOOD 0ESSELS IN ARTHRITISAngiogenesis+dynamic
process in RA that provides nutrients to expanding
synovium.Angiogenic factors, such as &*> and vascular
endothelial gro0th factor, can enhance blood vessel proliferation
in the synovium.3icrovascular endothelia in the synovium express
adhesion molecules that guide circulating cells into the !oint
under the influence of chemoattractants..andidate proinflammatory
functions of mast cells in rheumatoid synovitis. 3ast cell effector
functions suggest their participation in diverse pathogenic
path0ays in arthritis, including endothelial cell activation,
leu/ocyte recruitment and activation, synovial fi broblast
activation and hyperplasia, angiogenesis, and cartilage and bone
destruction. Activated mast cells elaborate mediators potently
capable of enhancing vasopermeability, including endothelial
expression of adhesion molecules, recruiting circulating
leu/ocytes, and activating infi ltrating leu/ocytes as 0ell as
resident macrophages, thereby contributing to the early phases of
infl ammatory arthritis. n chronic synovitis, mast cells synthesi;e
mitogens and cyto/ines that activate synovial fi broblasts, recruit
macrophages, and promote the gro0th of ne0 blood vessels,
implicating them in synovial lining hyperplasia and pannus
formation. 'urther, mast cells may participate in !oint destruction
by the induction of matrix metalloproteinases (33"s) from fi
broblasts, by activation of chondrocytes, and by direct and
indirect promotion of osteoclast differentiation and activation.
Because activated synovial fi broblasts demonstrate enhanced stem
cell factor (S.') expression, a potentially important positive
feedbac/ loop is established in 0hich S.' promotes mast cell
differentiation from progenitors and survival of mature mast cells,
leading to the mastocytosis described in infl amed synovium. #ote
that the importance of these candidate path0ays in vivo remains to
be established. bFGF, Basic fi broblast gro0th factorC IFN,
nterferonC IL, nterleu/inC MCP, 3onocyte chemoattractant proteinC
M-CSF, 3acrophage colony(stimulating factorC MIP, 3acrophage infl
ammatory proteinC PDGF, "latelet*derived gro0th factorC PMN,
"olymorphnuclear cellC Rank-L, Receptor activator of #'*B ligandC
TNF, Tumor necrosis factor. ('rom #igrovic "A, &ee 73. 3ast
cells in infl ammatory arthritis. Arthritis Res Ther $@@5CBE?(??.
2raphic design by Steve 3os/o0it;.) 3os/o0it;.)ADHESION MOLE-ULE
REGULATION "aracrine, !uxtacrine, and autocrine stimuli (left
column) and effector molecules (right column) of macrophage (3)
activation in RA. 3ost regulatory products of activated macrophages
also act on macrophages, resulting in autocrine regulatory loops
0ith relevance for disease severity and chronicity. 'B,
fibroblastsC -., endothelial cellsC #R, natural /iller cells. The
(=) in the T cell indicates the necessity of preactivating T cells
for effective stimulation of macrophages.yto/ine net0or/s and
cellular interactions in cartilage destruction in rheumatoid
arthritis. This scheme represents the progressive destruction of
the cartilage associated 0ith the invading synovial pannus in RA.
As a result of immune cell interactions involving T and B
lymphocytes, monocyteSmacrophages, and dendritic cells, a number of
different cyto/ines are produced in the infl amed synovium due to
the infl ux of infl ammatory cells from the circulation and
synovial cell hyperplasia. The upregulation of proinfl ammatory
cyto/ines produced primarily in the synovium, but also by
chondrocytes, result in the upregulation of cartilage*degrading
en;ymes, of the 33" and A7A3TS (A 7isintegrin And 3etalloproteinase
0ith Thrombospondin 3otifs) families, at the cartilage(pannus
!unction. .hemo/ines, nitric oxide, and prostaglandins also
contribute to the infl ammation and tissue catabolism. (Adapted
from Ftero 3, 2oldring 3B. .ells of the synovium in rheumatoid
arthritis. .hondrocytes. Arthritis Res Ther $@@BCTE$$@.)"apel de
T2'*U en la diferenciaci,n de las cOlulas T efectoras. -fecto del
T'2*U y molOculas implicadas en la diferenciaci,n y regulaci,n de
las distintas poblaciones de cOlulas T efectoras en relaci,n con su
funci,n dentro del sistema inmunitario. &E interleucinaC T2'*UE
factor de crecimiento transformador betaC TregE T reguladora.&a
3S en la AR contiene gran cantidad de&a 3S en la AR contiene
gran cantidad de cOlulas T cOlulas T1B 1B. Sin embargo, ha sido
dif%cil definir. Sin embargo, ha sido dif%cil definir el papel 6ue
estas desempePan en elel papel 6ue estas desempePan en el
mantenimiento y la propagaci,n de lamantenimiento y la propagaci,n
de la inflamaci,n articular. &a utili;aci,n en elinflamaci,n
articular. &a utili;aci,n en el tratamiento de la AR de una
prote%na detratamiento de la AR de una prote%na de fusi,n
.T&A*8 humano 6ue inhibe lafusi,n .T&A*8 humano 6ue inhibe
la coestimulaci,n T v%a .7$> ha proporcionadocoestimulaci,n T
v%a .7$> ha proporcionado una prueba indirecta pero contundente
de launa prueba indirecta pero contundente de la importancia de los
linfocitos T en la AR importancia de los linfocitos T en la AR1>
1>. -l. -l papel de T2'*U en la diferenciaci,n de laspapel de
T2'*U en la diferenciaci,n de las diferentes poblaciones de cOlulas
T humanasdiferentes poblaciones de cOlulas T humanas es mVltiple.
"or un lado, se ha demostradoes mVltiple. "or un lado, se ha
demostrado 6ue la sePali;aci,n a travOs de T2'*U?6ue la
sePali;aci,n a travOs de T2'*U? protege a las cOlulas T reguladoras
(Treg) deprotege a las cOlulas T reguladoras (Treg) de la apoptosis
la apoptosis1T 1T y es absolutamente necesariay es absolutamente
necesaria para inducir la expresi,n de 'oxp
