Hello immunologizer,
You didn?t tell me at which level you wanted your information, so
I?ve tried to include several levels in my answer. If this is not the
kind of information you were seeking, simply request an Answer
Clarification, and I will be glad to assist you further, if possible.
Most books do not place content online, so the majority of the
information here is from online articles.
Articles on RA (Rheumatoid Arthritis
====================================
Basic:
?The exact cause of rheumatoid arthritis is not known. It is
considered an autoimmune disease (see Autoimmune Disorders).
Components of the immune system attack the soft tissue that lines the
joints and can also attack connective tissue in many other parts of
the body, such as the blood vessels and lungs. Eventually, the
cartilage, bone, and ligaments of the joint erode, causing deformity,
instability, and scarring within the joint. The joints deteriorate at
a highly variable rate. Many factors, including genetic
predisposition, may influence the pattern of the disease.?
http://www.merck.com/mmhe/sec05/ch067/ch067b.html
?As with other forms of arthritis, rheumatoid arthritis involves
inflammation of the joints. A membrane called the synovium lines each
of your movable joints. When you have rheumatoid arthritis, white
blood cells ? whose normal job is to attack unwanted invaders such as
bacteria and viruses ? move from your bloodstream into your synovium.
There, these blood cells appear to play an important role in causing
the synovial membrane to become inflamed (synovitis).
This inflammation results in the release of proteins that, over months
or years, cause thickening of the synovium. These proteins can also
damage cartilage, bone, tendons and ligaments. Gradually, the joint
loses its shape and alignment. Eventually, it may be destroyed.
Some researchers suspect that rheumatoid arthritis is triggered by an
infection ? possibly a virus or bacterium ? in people with an
inherited susceptibility. Although the disease itself is not
inherited, certain genes that create an increased susceptibility are.
People who have inherited these genes won't necessarily develop
rheumatoid arthritis. But they may have more of a tendency to do so
than others. The severity of their disease may also depend on the
genes inherited. Some researchers also believe that hormones may be
involved in the development of rheumatoid arthritis.?
http://www.mayoclinic.com/invoke.cfm?objectid=09CF7868-4035-4B73-907328F854F7F0A3&dsection=3
TNF Alpha Inhibitors
?Your body naturally produces the protein TNF-alpha to mobilize your
white blood cells to fight infections and other invaders. This
temporarily causes inflammation in the affected area. Normally your
body would then get rid of the TNF-alpha. But if you have rheumatoid
arthritis or Crohn's disease, your body doesn't remove the TNF-alpha.
This causes more and more white blood cells to travel to the affected
area. As TNF-alpha continues to build up, it causes excess
inflammation, which can lead to pain and tissue damage.
TNF-alpha inhibitors block the action of TNF-alpha in your body. By
preventing TNF-alpha from acting, these drugs reduce inflammation and
other signs and symptoms you may have.
TNF-alpha inhibitors can't cure inflammatory conditions, such as
rheumatoid arthritis and Crohn's disease. But they can help you manage
the signs and symptoms of your disease.?
http://www.mayoclinic.com/invoke.cfm?objectid=377AEB3F-1180-496C-868804B50C9B8249&MOTT=DS00020
Basic Immunology of RA
?T lymphocytes are part of the immune surveillance system. They travel
through the bloodstream and lymphatic system, looking for foreign
substances (antigens) in the body. However, a T lymphocyte cannot
recognize an antigen unless it has been processed and ?presented? to
the T lymphocyte by another white blood cell, called an
antigen-presenting cell. Antigen-presenting cells consist of dendritic
cells (which are the most effective), macrophages, and B lymphocytes.
1.By itself, a T lymphocyte cannot recognize an antigen circulating in the body.
2.A cell that can process antigens, such as a dendritic cell, ingests the antigen.
3.Enzymes in the antigen-processing cell break the antigen into fragments.
4.Some antigen fragments are picked up by human leukocyte antigen
(HLA) molecules as they are assembled inside the antigen-processing
cell. Then the molecules with the antigen fragments are transported to
the cell's surface.
5.A special molecule called a T-cell receptor, which is located on the
surface of a T lymphocyte, can recognize the antigen fragment when it
is attached to and presented by an HLA molecule. The T-cell receptor
then attaches to the part of the HLA molecule presenting the antigen
fragment, fitting in it as a key fits in a lock.?
http://www.merck.com/mmhe/sec16/ch183/ch183a.html#sec16-ch183-ch183a-10
"Tens of millions of Americans experience the nagging pains and
physical limitations of the more than 100 forms of arthritis.
Rheumatoid arthritis is among the most debilitating of them all,
causing joints to ache and throb and eventually become deformed.
Sometimes these symptoms make even the simplest activities ? such as
opening a jar or taking a walk ? difficult to manage.
Unlike osteoarthritis, which results from wear and tear on your
joints, rheumatoid arthritis is an inflammatory condition. The exact
cause is unknown, but it's believed to be the body's immune system
attacking the synovium ? the tissue that lines your joints.
Rheumatoid arthritis affects about 2.1 million Americans. It's two to
three times more common in women than in men and generally strikes
between the ages of 20 and 50. But rheumatoid arthritis can also
affect young children and adults older than age 50."
http://www.cnn.com/HEALTH/library/DS/00020.html
The cause of RA has not been elucidated. Several possible associations
have been described. Associated factors may include the following:
Genetic predisposition
Female sex
Psychological stress
Immune response
Hormone interaction
Viral infection
Photo of a knee and hands on this page as well.
http://www.emedicine.com/EMERG/topic48.htm
?Rheumatoid arthritis (RA) is probably the autoimmune disease with
which most people are familiar. The suffix "itis" in arthritis means
inflammation, therefore inflammation of the joint ("arth" means
joint). Thus patients with rheumatoid arthritis have pain with motion,
swelling, and often redness and warmth of involved joints. Symptoms
result from the immune system's attack on the lining of the joint,
resulting in inflammation there or possibly in other internal organs.
This inflammation of the joint separates rheumatoid arthritis from
another common type of arthritis, osteoarthritis (OA). Generally
patients with osteoarthritis do not have signs of inflammation of the
joint but simply have pain as discussed below.
Like most autoimmune diseases, RA occurs predominantly in young to
middle-aged women. It tends to begin over a period of months,
initially affecting the small joints of the hands, and gradually
progressing to involve many joints throughout the body. Because this
is a systemic inflammatory disease, patients often have constitutional
symptoms such as fatigue, low grade fever, loss of appetite and
weight, and a general sense of ill health.
Rheumatoid arthritis is typically a chronic disease, but early
treatment by a rheumatologist can head off damage to the joint caused
by inflammation and thereby preserve joint function and reduce joint
pain. These treatments usually include such things as physical therapy
and instructions on exercise and joint protection, various
anti-inflammatory medications, judicious use of corticosteroids, and
sometimes stronger medicines to suppress the joint inflammation.?
http://www.musc.edu/rheumatology/FAQs/FAQ-RA.html
?Rheumatoid arthritis is a chronic systemic disease with articular and
extra-articular manifestations. Its clinical hallmark is a symmetrical
inflammatory polyarthritis affecting small proximal diarthrodial
joints. The abnormal laboratory finding characteristic of rheumatoid
arthritis is a positive rheumatoid factor (RF) (circulating
autoantibodies against the Fc portion of immunoglobulin G [IgG]).
Patients with high titers of RF are more likely to have rheumatoid
nodules, the typical histologic lesions of rheumatoid arthritis, as
well as extra-articular manifestations of disease that may affect
organ systems throughout the body, including the skin, eyes, lungs,
heart, and blood vessels.
Rheumatoid arthritis is a common disorder, affecting people of all
ethnic groups worldwide. An estimated 1% to 3% of people in the United
States have rheumatoid arthritis. The incidence of the disease
typically peaks during the fourth and fifth decades of life. As with
most other autoimmune disorders, it is more common in women than men,
with a female-male ratio of 3:1. The causes of rheumatoid arthritis
are unknown, but there is a genetic predisposition in that various
HLA-DR4 genotypes are associated with an increased incidence and
severity of disease in different populations (1). Although most cases
of rheumatoid arthritis are sporadic, the concordance rates in
monozygotic twins range from 15% to 30%.?
http://www.postgradmed.com/issues/2003/11_03/williams.htm
?In recent years a large number of proteins, termed cytokines, have
been identified as intercellular messengers in inflammation, immune
responses and tissue repair and remodeling. Dozens of these cytokines
and their cellular receptor sites have been discovered, cloned and
extensively studied in human disease. Many cytokines have been
classified as interleukins, interferons, colony stimulating factors,
growth factors and, of particular interest to the present discussion,
tissue necrosis factors (TNF). At least two forms of TNF exist, TNF-a
and b. Biological activities attributed to TNF-a include induction of
pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6;
enhancement of leukocyte migration by increasing endothelial layer
permeability; expression of adhesion molecules by endothelial cells
and leukocytes; activation of neutrophil and eosinophil functional
activity; fibroblast proliferation; synthesis of prostaglandins; and
induction of acute phase and other liver proteins. TNF-a is produced
by monocyte-macrophage lineage cells. Initially, this cytokine is
expressed as a 26-kDa membrane protein that is subsequently cleaved by
a metalloproteinase enzyme (TNF-a converting enzyme, TACE) to a 17-kD
soluble monomer. Association of these monomers into a homotrimer
yields TNF-a in its physiologically active form. Two cellular
receptors have thus far been identified for TNF-a, TNF-R1 (a 55-kDa
protein) and TNF-R2 (a 75-kDa protein). The R1 receptor is proposed to
mediate a variety of TNF-a actions related to proinflammatory actions
including cytotoxicity, fibroplast proliferation, synthesis of
eicosanoids, upregulation of adhesion molecules, etc. The function of
TNF-R2 is less well characterized. TNF-a receptors can be shed from
the cell surface, thereby competitively inhibiting the interaction of
TNF-a with membrane-bound receptor leading to stabilization of the
TNF-a molecule and providing a physiological mechanism for regulating
its effects.
Early preclinical studies of anti-TNF-a therapies demonstrated that
such intervention can reduce disease activity in colitis models and
decrease synovitis and joint erosions in animal models. Similarly,
these therapies were shown to prevent disease in transgenic mice that
develop polyarthritis as a result of constitutive expression of human
TNF-a and, when administered after disease onset, allows eroded joints
to heal. A variety of mechanisms for modulating the activity of TNF-a
have been investigated. Fusion proteins containing structural elements
of TNF-a receptors have been developed as circulating TNF-a
competitive inhibitors, thereby preventing the binding of the cytokine
to its cell surface receptors. One such protein, etanercept (Enbrel),
has recently been approved for the treatment of moderate to severe
rheumatoid arthritis. Alternatively, small molecule inhibitors of TACE
have been developed that are able to reduce TNF-a production. Also,
selective inhibitors of phosphodiesterase type IV have shown
anti-inflammatory activity in animal models, perhaps as a result of
the inhibition of cytokine (TNF-a, interleukins, interferons)
liberation. Lastly, anti-TNF-a mAbs have been developed which bind to
released TNF-a trimers as well as to membrane-bound cytokine. As a
result of this neutralizing interaction, the pathophysiological
actions of TNF-a are reduced. The presence of anti-TNF-a mAbs is also
reported to suppress production and secretion of TNF-a in patients.
One such antibody, infliximab, marketed as Remicade for IV injection,
is approved for the treatment of moderate to severe active Crohn's
disease and, in combination with methotrexate, for the treatment of
rheumatoid arthritis (RA).?
http://www.uspharmacist.com/oldformat.asp?url=newlook/files/Feat/Monoclonal.htm&pub_id=8&article_id=784
?RA should not be confused with other forms of arthritis, such as
osteoarthritis or arthritis associated with infections. RA is an
autoimmune disease. This means that the body?s immune system
mistakenly attacks the tissues it is supposed to protect.
The immune system produces specialized cells and chemicals, which are
released into the bloodstream and begin to attack body tissues.
This response causes abnormal growth and inflammation in the synovium,
the membrane that lines the joint. This process is called synovitis
and is the hallmark of an inflammatory arthritis such as RA.
As the synovitis expands inside and outside of the joint, it can
damage the bone and cartilage of the joint and the surrounding
tissues, such as ligaments, tendons, nerves, and blood vessels.?
http://www.emedicinehealth.com/articles/37138-1.asp
RHEUMATOID ARTHRITIS AND AUTOIMMUNITY: A new approach to their cause &
how long term cure might be achieved
?In autoimmune conditions, such as rheumatoid arthritis, the body
produces antibodies to its own tissues - "autoantibodies". Until now
it has not been clear why people make autoantibodies or whether
autoantibodies cause the illness. This webpage gives an new
explanation for autoimmunity and suggests a new treatment that may
produce long term relief for conditions such as rheumatoid arthritis
and lupus. Promising results obtained in early trials of this
treatment are summarised on the linked page "Update on B cell
depletion therapy.
Our conclusion is that autoantbodies are first made by chance but can
set up a vicious cycle so that they go on being produced in large
amounts, causing damage to body tissues. Removing the cells that make
antibodies should break this cycle. It is now possible to remove most
of these cells safely and effectively. Although we almost certainly
need to increase the power of the treatment to remove all the unwanted
cells, preliminary results are encouraging.?
http://www.ucl.ac.uk/~regfjxe/Arthritis.htm
?We have established the role of an alternative pathway of antigen
presentation to T lymphocytes in immunity to infection. This pathway
presents certain T cell epitopes very rapidly and seems to be
dependent on the structural context of the epitope within the protein
antigen. The ribbon diagram shows a monomer of the Caf1-capsular
protein of Yersinia pestis, a component of the subunit plague vaccine.
The core of CD4 T cell epitopes we have mapped are marked in colour
together with their position in the amino acid sequence of Caf1. It
can be seen that epitope10-19 is located on a flexible amino-terminal
extension of the Caf1 monomer, in contrast to the remaining four
epitopes. We have demonstrated that epitope 10-19 is processed by the
alternative pathway of antigen presentation which thus correlates with
its exposed position in the Caf1 monomer.?
http://www.ncl.ac.uk/medi/research/rheumatology/research_activity/teams/prog3/team6.htm
http://www.ncl.ac.uk/medi/research/rheumatology/research_activity/
?Although the etiology of the disease remains unknown, our
increasing knowledge of the mechanisms underlying pathogenic events in
rheumatoid synovitis, has provided opportunities to specifically
target cell surface markers or cytokines involved in the inflammatory
response. The objective of this review is to describe the different
therapeutic approaches with biological agents that are either being
utilized or are under development. Some of these products reflect the
evolving capacity for the biotechnology industry to synthesize and
humanize therapeutic agents: anti-tumor necrosis factor (TNF) a
monoclonal antibodies (MoAb) and recombinant TNF-receptor construct
appear to be validated tools. These treatments alone, or in
combination with methotrexate are very effective in rheumatoid
patients. Data from clinical trials and issues related to mechanisms
of action, potential toxicity, and future perspectives for these novel
therapeutic options are considered in this review. Anti-cytokine
treatment include other interesting approaches to interfere with
on-going inflammatory processes, such as the use of recombinant human
interleukin (IL)1 recept`r antagonist, or recombinant human IL10. T
cell costimulatory blockade, induction of apoptosis in the synovial
tissue, and gene therapy could represent future strategies in
rheumatoid disease.?
http://www.bentham.org/cdtiemd1-1/afeltra/afeltra_.htm
?There are two popular theories regarding the pathogenesis of
rheumatoid arthritis (RA). The first holds that the T cell, through
interaction with an - as yet unidentified - antigen, is the primary
cell responsible for initiating the disease as well as for driving the
chronic inflammatory process. This theory is based upon the known
association of RA with class II major histocompatability antigens, the
large number of CD4+ T cells and skewed T cell receptor gene usage in
the RA synovium. The second theory holds that, while T cells may be
important in initiating the disease, chronic inflammation is
self-perpetuated by macrophages and fibroblasts in a T-cell
independent manner. This theory is based upon the relative absence of
activated T cells phenotypes in chronic RA and the preponderance of
activated macrophage and fibroblast phenotypes.?
Inflammatory mediators in RA
?In addition to activating synovial cells to secrete inflammatory
mediators (slide), IL-1 and TNF also have profound systemic effects
(slide). For example, increased systemic levels of TNF and IL-1 are
associated with fever, muscle wasting and decreased appetite. Some of
these effects are mediated via the induction of IL-6 synthesis.
Mature plasma cells that secrete rheumatoid factor are another
prominent cellular component of rheumatoid synovium. The stimulus for
maturation of B cells to immunoglobulin-secreting plasma cells has
classically been ascribed to CD4+ T cells; however, as already noted,
CD4+ T cells are not activated in the chronic phase of rheumatoid
arthritis. IL-6, however, is a potent stimulus for maturation of B
cells to plasma cells. Thus, synovial fibroblasts are likely providing
the "T cell independent" stimulus for continuous plasma cell
activation and rheumatoid factor production. IL-6 also suppresses
albumin synthesis by the liver and stimulates acute phase protein
synthesis. IL-6, therefore, contributes significantly to ESR
elevation.
Neutrophils are recruited in very large numbers to the rheumatoid
cavity where they can be aspirated in the synovial fluid. Complement
activation is not a prominent feature of RA. Therefore, C5a is
unlikely to contribute significantly to the recruitment of neutrophils
to the joint. IL-8, however, is also a potent and specific chemotactic
stimulus for neutrophils (slide). Since synovial fibroblasts line the
joint cavity, their elaboration of this cytokine into the joint cavity
is likely to explain the selective recruitment of neutrophils to the
synovial cavity. Neutrophils in the synovial fluid are in an activated
state, releasing oxygen-derived free radicals that depolymerize
hyaluronic acid and inactivate endogenous inhibitors of proteases,
thus promoting damage to the joint.?
http://www.hopkins-arthritis.som.jhmi.edu/rheumatoid/rheum_clin_path.html
?Rheumatoid arthritis comes in many guises. Dottie Weyant has the
disease, but you'd never guess it if you met her. Diagnosed soon after
symptoms first appeared 10 years ago, when she was 50, she
participated in a study of a new medication. Dottie did so well that
she not only continues to work as a waitress, but also walks three
miles every day. Fred Jones, a pseudonym for a man now in his
late-50s, has battled the disease for decades. He tried one medication
after another, but none seemed to work effectively. As his disease
progressed, he had to quit working. He was beginning to give up hope
when he tried a medication approved only last year by the U.S. Food
and Drug Administration. His symptoms finally responded, and his
quality of life has improved enormously.?
http://www.rheumatology.org/public/USAToday/rheumatoid.asp?aud=pat
Modulation of immune function by dietary lectins in rheumatoid arthritis.
Br J Nutr 2000 Mar;83(3):207-17
Cordain L, Toohey L, Smith MJ, Hickey MS.
Department of Health and Exercise Science, Colorado State University,
Fort Collins 80523, USA. cordain@cahs.colostate.edu
?Despite the almost universal clinical observation that inflammation
of the gut is frequently associated with inflammation of the joints
and vice versa, the nature of this relationship remains elusive. In
the present review, we provide evidence for how the interaction of
dietary lectins with enterocytes and lymphocytes may facilitate the
translocation of both dietary and gut-derived pathogenic antigens to
peripheral tissues, which in turn causes persistent peripheral
antigenic stimulation. In genetically susceptible individuals, this
antigenic stimulation may ultimately result in the expression of overt
rheumatoid arthritis (RA) via molecular mimicry, a process whereby
foreign peptides, similar in structure to endogenous peptides, may
cause antibodies or T-lymphocytes to cross-react with both foreign and
endogenous peptides and thereby break immunological tolerance. By
eliminating dietary elements, particularly lectins, which adversely
influence both enterocyte and lymphocyte structure and function, it is
proposed that the peripheral antigenic stimulus (both pathogenic and
dietary) will be reduced and thereby result in a diminution of disease
symptoms in certain patients with RA.?
http://www.dadamo.com/knowbase/lectin/lect3.htm
?Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory
systemic disease of unknown etiology characterized by persistent joint
inflammation that results in progressive joint destruction, joint
deformity, and physical disability.1 RA may affect other organs and
may also result in an increased risk for premature death. The average
life expectancy of RA patients is decreased by 3 to 18 years compared
to age and gender matched controls.2 Damage to the bone and cartilage
caused by intense episodic synovitis in RA can be attributed to
various potent proinflammatory mediators known as cytokines that
include interleukin?1 (IL?1), tumor necrosis factor?a (TNF?a), as well
as several other cytokines?
There is also an excellent illustration on this page, showing the
involvement of TNF (tumor necrotizing factor). IL-1 and pathogenesis
of RA. There are others also on this page.
http://www.hopkins-arthritis.som.jhmi.edu/rheumatoid/il1.html
TNF Antibodies and RA
http://www.jr2.ox.ac.uk/bandolier/band99/b99-2.html
Studies
=======
A Genomewide Screen in Multiplex Rheumatoid Arthritis Families Suggests
Genetic Overlap with Other Autoimmune Diseases
?Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with
a complex genetic component.We report the first major genomewide
screen of multiplex families with RA gathered in the United States.
The North American Rheumatoid Arthritis Consortium, using well-defined
clinical criteria, has collected 257 families containing 301 affected
sibling pairs with RA. A genome screen for allele sharing was
performed, using 379 microsatellite markers.?
http://nslij-genetics.org/pub/jawaheer-ajhg-2001.pdf
?Human leucocyte antigen (HLA) class II molecules have been shown
to be associated with predisposition to rheumatoid arthritis (RA). We
generated HLA-DR and DQ transgenic mice that lacked endogenous class
II molecules to study the interaction between the DR and DQ molecules
and define the immunologic mechanisms in rheumatoid arthritis. Using
collagen-induced arthritis (CIA) as an experimental model for
inflammatory polyarthritis, we show that both DQ and DR are involved
in predisposition or resistance to arthritis. Our studies suggest that
polymorphism in DQB1 genes may determine predisposition to RA while
the DRB1 polymorphism may dictate severity/protection of the disease.
These mice provide powerful tools to develop immunotherapeutic
protocols.?
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=130003
?Two proinflammatory cytokines may contribute to the severity of
rheumatoid arthritis (RA). And, according to researchers, the
anti-inflammatory cyctokine interleukin (IL)-10 does little to counter
this action.
Tumour necrosis factor a (TNF-a) and IL-6 may be implicated in the
imbalance of coagulation and fibrinolysis in favour of coagulation and
the impairment of the adhesive molecule pathway in RA.
Researchers studied the relationship between pro- and
anti-inflammatory cytokines to disease activity, coagulation and
fibrinolytic variables and circulating intercellular adhesive
molecule-1 (cICAM-1). The study was designed to provide a better
understanding of the cascade of events, which are implicated in the
inflammatory process in rheumatoid arthritis.
Participants included 45 patients with rheumatoid arthritis and 33
healthy subjects. TNF-a, IL-6 and IL-10, cICAM-1, tissue-type
plasminogen activator (t-PA), plasminogen activator inhibitor-1
(PAI-1) and D-dimer antigens were measured in their blood by
enzyme-linked immunosorbent assay (ELISA) test.?
http://arthritis.about.com/gi/dynamic/offsite.htm?zi=1/XJ&sdn=arthritis&zu=http%3A%2F%2Fwww.docguide.com%2Fnews%2Fcontent.nsf%2Fnews%2F3F0073DB3BC341908525698B006EB1F5%3FOpenDocument%26c%3D%26count%3D10%26id%3D48dde4a73e09a969852568880078c249
Assessing Prognosis in Rheumatoid Arthritis using Monoclonal
Antibodies and Flow Cytometry
http://www.tnblabs.com/RAsumPap.html
Books
=====
Rheumatic Diseases: Immunological Mechanisms And Prospects For New
Therapies, (1999) Edited by J. S. Hill Gaston, Cambridge Press. 288
pages Reviewed for BloodLine by Sulaiman George Gegbe, Department of
Clinical Haematology, West Suffolk Cambridge Postgraduate Teaching
Hospital Trust Kingston, U.K.
?The authors further discussed (chapter 2) T cell immunity and how HLA
subtypes and their genetic codes are linked to specific examples of
rheumatic diseases such as RA & IDDM. The role of MHC in Autoimmunity
(chapter 3) was then explored, with the authors indulging into the
complex association of HLA gene cluster of chromosome 6p21.3 (classes
I, II & III) and their relative risk contribution to autoimmunity
through MHC. The relative Location and function of TNF-a, TNF-b,
HSP-70, Al, B8, Cw7, C4A, 21OH, TAPs, LMPs regions on HLA was well
documented in the text. The structure of HLA and trimolecular complex
was used to explain the relationship between both HLAI & HLAII
heterodimer (8-b, 2-a) peptide binding site in relationship to their
crystallography and in association with epidemiology. The Function of
class MHC I and II in Processing of antigen in endoplasmic reticulum
and the function of CLIPS and TAPS was made clear and the Comparison
of MHC I and MHCII based on TCR functional and structural CD4 &CD8
molecules was properly elaborated on.
The hunt for therapy was extended to using epidemiological data to
established the relative risk relationship between HLA found in
Inflammatory Bowel Disease, Ankylosing Spondylytis, Psoriatic
Arthritis, Rheumatoid Arthritis, Systemic lupus, Sjogen syndrome,
periarticular arthritis, juvenile arthritis and juvenile
dermatomyositis in relation to racial difference and sited references
using dizygotic & monozygotic twins, concordance, penetrance and
population studies. In depth knowledge about the significant
association of RA and HLA DR4 halotypes, immune mediated blistering
phemiphegus disease, multiple sclerosis and DRB1 & DQB was clearly
acknowledged. The authors also revel into the aspect of
transcomplementation of HLA dimers with additional reference to
coeliac disease. The authors also thrive to explain the mechanism by
which HLA may be attributed to autoimmunity and the concept of how
disease associated alleles can give rise to unique peptide binding
with reference to crystallography of binding pockets and how peptide
binding motifs can be altered due to alleleic difference
Although there is prospect for new therapies, the authors also manage
to mention some set backs such as the slow elucidation of the antigen
processing mechanism and explained known factors that affect
processing.?
http://www.bloodline.net/stories/storyReader$3295
?Subsumed under the term "rheumatoid factors" (RF) are autoantibodies
of the IgM, IgA and IgG isotype which are reactive with the
crystallizable fragment (Fc fragment) of IgG.1
Largely of historical interest are the assays for RF, which employ
human IgG coated on latex particles (latex fixation) or rabbit IgG
coated on sheep red blood cells (sheep cell agglutination titer,
SCAT). The SCAT is less sensitive but more specific for RA than latex
fixation. The method of choice for detection of RF is nephelometry
which provides a continuous readout of results in IU/mL as opposed to
the discontinuous readout (doubling dilutions to endpoint) of latex
fixation or SCAT which can only detect changes in concentration of 50%
or greater. With nephelometry, CVs at the cutoff for normal are
routinely <7% vs. CVs of >100% by doubling dilution titration.2 Most
commercially available reagents for nephelometric quantitation of RF
detect all three isotypes. IgM RF (<7.5 IU/mL) are found in 2-10% of
apparently healthy Caucasian adults (generally <5%). The cut-off for
adults increases with age but is as yet not well established by
nephelometry or EIA.3 Cut-offs are not well established for children
of different ages, but <10 IU/mL is probably a useful guide.
That RF might be an early marker of the pathogenetic process in RA is
supported by data showing that the risk of developing RA increases in
proportion to the concentration of RF in normals.4,5 RF-positive
arthritis (but not RF-negative erosive arthritis) and "false-positive
RF" titers (SCAT) are associated with increased risk of death or
cardiovascular death, respectively.
RF are found in 50-90% of classical RA;6 concentrations are higher in
active disease and correlate inversely with functional capacity.7 RF
are also found in Sjögren syndrome (75-95%), MCTD (50-60%), IgA
nephropathy (25-40%),8 cryoglobulinemia (variable percent depending on
type),9 SLE (15-35%), systemic sclerosis (20-30%) and PM/DM (5-10%).
Unlike agglutination tests, RF of the IgM, IgA and IgG isotypes can be
individually quantitated by EIA.10 The clinical utility for specific
detection of the different isotypes of RF is becoming increasingly
well documented. For example, the previously reported correlations
between raised RF and extra-articular manifestations in RA (mucosal &
secretory problems and bone erosions) largely reflect the presence of
IgA RF, but not IgM RF or IgG RF.11,12 In RA, IgM RF are the
predominant isotype; other isotypes are generally present in lower
frequency and quantity.10 IgM RF generally appear in serum in 85-90%
of RA patients within 1 year of disease onset. It is unusual to have
all three isotypes of RF present in diseases other than RA.
The fact that many RF resemble Staphylococcus aureus protein A in
reacting with IgG1, 2 and 4 but not with IgG3 might mean that RF arise
as anti-idiotypic autoantibodies to antibodies reactive with bacterial
Fc-binding proteins. Other possibilities are suggested.
Combined detection of RF and antiperinuclear factor (APF) yields
predictive values of ~94% for RA or non-RA; detection of APF greatly
decreases the number of seronegative RA.17 Other autoantibodies, which
may assist in the diagnosis of RA have been studied but do not appear
to provide much additional diagnostic information.18 Anti-SA,
anti-filaggrin antibody (AFA) and anti-cyclic citrullinated peptide
(anti-CCP) had a specificity of >90% but a sensitivity of <50% for RA.
Other autoantibodies tested include calpastatin and anti-keratin
antibody (AKA). 18 The affinity maturation and class switching
characteristic of the RF of patients with RA are not found in RF of
normals or RF of immunized donors.19 Perhaps the affinity of RF is
related to their pathogeneticity, as is the case with autoantibodies
to dsDNA.?
Rheumatology, by Dr. James Peter, M.D., Ph.D.
http://www.specialtylabs.com/books/chapters.asp?id=5
Immunological Aspects of the Vascular Endothelium, Series: Cambridge
Reviews in Clinical Immunology, Edited by Caroline O. S. Savage
University of Birmingham, Jeremy D. Pearson, King's College London
(ISBN-10: 052145249X | ISBN-13: 9780521452496)
Published September 1995
?This is the first volume to take an in-depth look at the functioning
of the vascular endothelium, and the diseases and tissue injury that
arise as a result of inflammation and immunological responses. The
vascular endothelium is a metabolically highly active layer of cells
lining all blood vessel walls. Through its interactions with
leucocytes and other mediators, it is central to the development of
inflammatory foci and to lymphocyte trafficking around the body.
Tissue injury may arise here as a result of abnormal inflammatory or
immune responses. The potential for such injury to contribute to
autoimmune disease is discussed in this book, particularly in relation
to autoimmune vascular disease of the renal, rheumatological and
neurological systems, as well as in organ transplantation.
? Spans basic science and medical diseases
? Includes review of current concepts of inflammation and immunity
? Of importance to transplantation medicine
http://www.cambridge.org/uk/catalogue/catalogue.asp?isbn=052145249X
Diagnosis
==========
?To find out whether you have arthritis, a doctor will take your
medical history and do a physical examination. He or she may also have
X-rays or other imaging procedures done along with blood and lab
tests. Lab tests may include:
Antinuclear antibody (ANA) test to check levels of antibodies in the blood
Sampling the synovial fluid, which surrounds and lubricates the
joints, to see if it has crystals, bacteria or viruses
Complete blood counts to see if white blood cell, red blood cell and
platelet levels are normal
Creatinine to monitor for underlying kidney disease
Erythrocyte sedimentation rate to detect inflammation
Rheumatoid factor test to determine if rheumatoid factor is present in the blood
Urinalysis to determine levels of protein, red blood cells, white
blood cells, and casts
http://www.csmc.edu/5234.html
Images
======
Numerous images and charts of Apoptosis in Human Rheumatoid Arthritis
Synoviocytes with Cyclooxygenase-2 Overexpression and effects of
Diosgenin, a plant steroid.
http://www.medscape.com/content/2004/00/48/12/481267/481267_fig.html
Pathogenesis of RA
http://www.ucl.ac.uk/~regfjxe/RA.gif
IgG Rheumatoid factor production
http://www.ucl.ac.uk/~regfjxe/RF.gif
Joints
http://www.arc.org.uk/about_arth/booklets/6033/images/6033_2.gif
http://www.hopkins-arthritis.som.jhmi.edu/radrds/radiology_6/images/slide3.jpg
http://www.yourdictionary.com/images/ahd/jpg/A4rheumt.jpg
Juvenile RA
http://www.emedicinehealth.com/images/4453/4453-4463-34647-34905.jpg
Therapy Algorithm
http://www.arthritis.co.za/images/dmard.2.gif
Joints affected by RA
http://www.mydr.com.au/content/images/categories/arthritis/RA_joints_involved.jpg
Hands
http://medicine.ucsd.edu/clinicalmed/upper-rheumatoid-arthritis.JPG
http://www.csmc.edu/5234.html
x-ray
http://medinfo.ufl.edu/~bms5191/ortho/images/ra1.jpg
http://www.meddean.luc.edu/lumen/MedEd/Medicine/Rheumatology/Hands/Hand5/Hand5dx.html
Pie Chart
http://www.arc.org.uk/about_arth/booklets/6033/images/6033_3.gif
Immunotherapy in RA
http://www.ncl.ac.uk/medi/research/rheumatology/research_activity/teams/prog3/isaac_slide.htm
Antibodies
Immunoglobulins and complement scheme
http://www.bentham.org/cdtiemd1-1/afeltra/f1-p46.jpg
http://www.hopkins-arthritis.som.jhmi.edu/edu/acr/images/flow_ra_man.gif
Medicines, including immunosuppressants
http://www.merck.com/mrkshared/mmanual_home2/dtb/dtb067_1.gif
Additional Information:
RA Glossary
http://www.cambridgeantibody.com/html/glossary
These sites may interest you:
http://www.rheumatology.org/
http://www.rheumatology.org/public/factsheets/ra_new.asp?aud=pat
Johns Hopkins Arthritis
http://www.hopkins-arthritis.som.jhmi.edu/edu/acr/acr.html
I certainly hope this is the type of information you were seeking.
Again, before rating, please request an Answer Clarification, if
anything needs clearing up.
Sincerely, Crabcakes
Search Terms
Immunological aspects RA
Immunopathogenesis of RA
RA + Inflammation
Rheumatology
Monoclonal antibodies + RA
TNF + RA |
