Figure
1: Example of rheumatoid arthritis effects.
Retrieved from Cedars-Sinai (2013) (http://www.cedars-sinai.edu/Patients/Health-Conditions/Arthritis---Rheumatoid-Arthritis-Osteoarthritis-and-Spinal-Arthritis.aspx)
You’ve likely heard of rheumatoid
arthritis (RA), an autoimmune disease that results in a chronic, systemic
inflammatory disorder. More than 2 million adults in the United States suffer
from this disease, with women being two to three times more likely to develop
it than men (UCSF Medical Center 2013; http://www.ucsfhealth.org/conditions/rheumatoid_arthritis/). The disease
can occur at any age, although it typically affects those over 40 years old
(Mayo Clinic 2013; http://www.mayoclinic.com/health/rheumatoid-arthritis/DS00020). RA is caused
by an autoimmune attack on antigens expressed in the synovial tissue and
cartilage of joints. Wrists, fingers, knees, feet, and ankles are most commonly
affected. Early phase symptoms are characterized by morning stiffness in the
affected joints. Over time, inflammation, cartilage destruction, and bone
erosion may lead to deformations and crippling. The general explanation for
these effects is as follows. The immune system attacks the synovium, which is
the lining of the membrane that surrounds joints. Inflammation ensues which
results in the thickening of the synovium and can eventually lead to the
destruction of the cartilage and bone within the joint. The tendons and
ligaments that hold the joint together also weaken and stretch, and can suffer
degradation as a result of proteases (enzymes that break down proteins)
secreted by activated macrophages (phagocyte meaning that they engulf solid
particles). In this fashion, the joint gradually loses its shape and alignment,
leading to deformities and crippling.
Figure 2: RA commonly affected joints and
impact on joints.
Retrieved from Atlantic Apothecary
(2013) (http://www.atlanticapothecary.com/disease-state-management/arthritis/rheumatoid-arthritis/)
So, more specifically, how does this all
happen? Activated macrophages and DCs extravasate (essentially escape from a
blood vessel into tissues) into the joint and produce large amounts of
pro-inflammatory cytokines (intercellular mediators), especially TNF. The blood
vessels in the inflamed joint take on the characteristics of high endothelial
venules (HEVs), which specializes them for lymphocyte (small white blood cell)
extravasation (Villani 2012; http://www.ipbs.fr/?High-endothelial-venules-HEVs). The
inflammation is perpetuated by the eventual infiltration of the joint by CD4+
Th effectors (white blood cells that assist other immune cells) and CD8+
CTLs (white blood cells responsible for causing cell death of infected/damaged
cells), which produce cytokines like TNF and IL-17. RA synovial tissues also
contain “ectopic” germinal centers (sites where mature B lymphocytes
proliferate, differentiate, and mutate and switch the class of their
antibodies), meaning that these structures have developed in the wrong tissue. Plasma
cells in these abnormal germinal centers produce autoantibodies (an antibody
formed in response to and reacting against an antigenic constituent of its own
tissues) directed against antigens (substance that induces an immune antibody
response) in the synovial membrane and cartilage. Common markers of RA include
the presence of rheumatoid factor and anti-citrullinated protein antibodies
(ACPA) in the serum. These markers represent autoantibodies that have
significant diagnostic values (da Mota et al. 2012; http://www.ncbi.nlm.nih.gov/pubmed/22187055).
Figure 3: General immune overview of RA
joint. Retrieved from Nutrition Remarks (2013) (http://www.nutritionremarks.com/2013/03/09/fish-oil-can-reduce-rheumatoid-arthritis-flu/)
ACPAs are autoantibodies present in the
majority of patients with RA. They have proven to be useful biomarkers and
allow for the diagnoses of RA at an early stage (da Mota et al. 2012; http://www.ncbi.nlm.nih.gov/pubmed/22187055). During
inflammation, in a process known as citrullination, arginine residues in
proteins can be converted to citrulline ones (Suurmond et al. 2011; http://www.ncbi.nlm.nih.gov/pubmed/21339220). If this
change significantly alters the shape of the proteins, they may be seen as
antigens and an immune response will be generated. Autoantibodies are generated
against these citrullinated proteins (including fibrinogen or vimentin for
example), forming the basis of an autoimmune disease. It is important to note
that rheumatoid arthritis patients can be either ACPA-positive or
ACPA-negative, and this status can have a significant influence on the
intensity and therapy of RA. In fact, ACPA-positive and ACPA-negative RA have
been recognized as distinct disease sub-entities, which demonstrate significant
differences with regards to HLA-association, genetic and environmental risk
factors, disease phenotype, and treatment response.
Commonly used biological therapies for
RA target mainly cytokine pathways. However, abatacept is a chimerical CTLA4
(protein receptor on the surface of T cells which acts as an off switch for T
cell attack) and IgG Fc (antibody isotype) fusion protein modulating T cell
activation. Abatacept is thought to work by blocking CD28 costimulation, and
consequently interfering with T cell-APC interaction and limiting T cell
activation. CD28 is a molecule expressed on T cells that provides co-stimulatory
signals by interacting with B7 (peripheral membrane protein key for
costimulation signals) molecules CD80 and CD86 on antigen presenting cells
(APCs). CD28 is thus required for T cell activation. This abatacept mediated
blockade could potentially change the activity and lifespan of APCs and limit
the activation of CD4+ T cells. Using abatacept has been associated
with reduced joint inflammation and pain and joint damage in patients with
active RA (Maxwell & Singh 2009; http://www.ncbi.nlm.nih.gov/pubmed/19821401).
Figure 4: Abatacept functional
mechanism. Retrieved from Rheumatologist (2011) (http://www.rheumatologysa.com/biologics.html)
In their August 2013 paper (http://www.biomedcentral.com/1471-2172/14/34), Pieper et al.
examined T cell functionality in the context of ACPA status in RA patients with
regards to abatacept therapy. The authors recognized that RA has a strong MHC
class II (molecules on APCs and B cell lymphocytes) component, indicative of a
HLA (human leukocyte antigen; the genes encoding the MHC in humans) associated
autoimmune disease, which implies that CD4+ T cells are important.
This is also supported by the presence of ACPAs in patients and the fact that
CD4+ T cells are abundant in synovial tissue and fluid. The role of
CD4+ T cells in RA may be mediated through Th1 effector functions
(enhanced cytotoxic mechanisms), such as IFN-γ secretion, Th17 activity, or
induction of ACPA. It has also been suggested that regulatory T cell function
is impaired in RA. Tregs are important as they serve as T cells that modulate
the immune system. In this study, the authors wanted to look at the effect of
abatacept therapy on T cell subsets and their associated cytokines in
ACPA-positive versus negative patients. They accomplished this by performing an
anti-CCP assay to determine anti-CCP levels in the patients. They also
performed intracellular cytokine staining and luminex analysis of cell culture
supernatants to examine cytokine levels. Treg levels were analyzed and
phenotypically characterized in peripheral blood mononuclear cells by flow
cytometry. Finally, synovial fluid mononuclear cells were examined in vitro in
the presence or absence of abatacept.
Figure 5: T
cell subsets. Retrieved from Peterson (2012) (http://livingwellnessblog.wordpress.com/2012/10/12/am-i-th1-or-th2-or-th17/)
This study examined 33 patients starting
on abatacept therapy, 23 of whom were ACPA-positive and 10 of whom were
ACPA-negative. Peripheral blood was collected from these patients at baseline,
after 3 months, and after 6 months. The authors noted diminished T cell
effector functions in patients treated with abatacept. Specifically, the
authors began by investigating IFN-γ, TNF, and IL-17 as these cytokines are the
most relevant in the context of RA, are implicated in disease pathogenesis, and
are central in Th1 and Th17 function. T cells of the Th1 subset were found to
be affected by abatacept, as both TNF and IFN-γ production by CD4+ T
cells decreased. IL-17A production exhibited a decreasing trend. In contrast,
in ACPA-negative patients, increases in TNF, IFN-γ, and IL-17A production were
noted (reduced cytokine output).
Abatacept limits the immune response by
binding to CD80 and CD86 (B7 proteins) on APCs. Consequently, the authors
further examined the effect of abatacept on key cytokines influencing Th1, Th2,
and Th17 subsets. The general trend was a decrease in cytokine levels (most
notably IL-3, IL-13, IL-23) in ACPA-positive patients, while an increase in
cytokine levels (most notably IFN-γ) was observed in ACPA-negative patients.
The impact of abatacept on regulatory T cell frequencies in vivo was also
examined. This was accomplished by investigated FOXP3, Helios, CD39, CTLA4, and
CD45RA as these proteins have all been implicated in Treg function in RA. All
Treg subset frequencies were considerably reduced. To assess the impact of
abatacept on T cells and Tregs in the synovial fluid of affected joints, the
authors examined the affect of in vitro added abatacept on both synovial T
effector and Treg function. Ultimately, the authors found that abatacept
reduces T cell proliferation. A general reduction in Treg frequency in the
periphery was also noted.
This study demonstrated a significant
down-regulation of all key T cell effector subsets by abatacept, but only in
APCA-positive patients. A general decrease in Treg cell frequency was also
observed. Ultimately, the study sought to tease out the impact of the abatacept
costimulation blockade on cell population level. The authors accomplished this using
both peripheral blood and synovial fluid cells. Most strikingly, a reduction in
representative Th1, Th2, and Th17 cytokines was observed in ACPA-positive patients,
but not in negative ones. Overall, abatacept was found to have a significant
impact on T effector functions of the Th1, Th2, and Th17 subsets and the
effects were predominantly observed in ACPA-positive patients. These findings
demonstrate that RA is a disease with several-different sub-entities, and
support the notion that ACPA-positive and ACPA-negative patients represent
immunologically distinct disease phenotypes and require tailored treatment
strategies.
This paper is highly relevant because of
the significant impact of RA in the world today. Many of us know someone who
suffers from this immune disease and have seen how debilitating it can be. For
that reason, it is important that we continue to investigate potential
treatments for this disease and analyze the mechanisms fueling these
treatments. This study provided insight into how the abatacept costimulation
blockade can modulate T cell effector functions. The better we understand the
mechanism of action and effects of a treatment, the more effectively we will be
able to determine what treatments will work best. This study also points out
the complexity of RA in that it can be characterized by immunologically distinct
disease phenotypes. This can have repercussions for which treatment strategies
should be employed, as certain treatment methods may work better with a certain
disease phenotype, as this study demonstrated. Further studies should work to
expand upon the direction of this study and examine the mechanistic effects of
other RA therapies and how effective the therapy is in relation to different RA
disease phenotypes. In this way, the most effective therapy can be matched to
different RA disease phenotypes. Although this study indicates that abatacept
therapy effectively modulates T cell effector functions in ACPA-positive
patients, further studies should seek to identify a more effective treatment
for ACPA-negative patients.
References:
Primary Article:
Pieper, J.,
Herrath, J., Raghavan, S., Muhammad, K., van Vollenhoben, R., & Malmstrom,
V. (2013). CTLA4-Ig (abatacept) therapy modulates T cell effector functions in
autoantibody-positive rheumatoid arthritis patients. BMC Immunology, 14(34). http://www.biomedcentral.com/1471-2172/14/34.
Additional Sources:
da Mota, L.M.,
Dos Santos Neto, L.L., de Carvalho, J.F., Pereira, I.A., Burlingame, R.,
Menard, H.A., & Laurindo, I.M. (2012). The presence of anti-citrullinated
protein antibodies (ACPA) and rheumatoid factor on patients with rheumatoid
arthritis (RA) does not interfere with the chance of clinical remission in a
follow-up of 3 years. Rheumatol. Int., 32(12):
3807-3812. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22187055.
Maxwell, L.
& Singh, J.A. (2009). Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev., 4:
CD007277. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19821401.
Mayo Clinic.
(2013). Rheumatoid arthritis. Mayo
Foundation for Medical Education and Research. Retrieved from http://www.mayoclinic.com/health/rheumatoid-arthritis/DS00020.
Suurmond, J., Schuerwegh, A.J, & Toes, R.E. (2011). Anti-citrullinated protein antibodies in rheumatoid arthritis: a functional role for mast cells and basophils? Ann. Rheum. Dis., 70: 55-58. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21339220.
UCSF Medical
Center. (2013). Rheumatoid arthritis. The
Regents of the University of California. Retrieved from http://www.ucsfhealth.org/conditions/rheumatoid_arthritis/.
Villani, G.G.
(2012). High endothelial venules (HEVs), specialized blood vessels for
lymphocyte migration. Institute of
Pharmacology and Structural Biology. Retrieved from http://www.ipbs.fr/?High-endothelial-venules-HEVs.
Images:
Atlantic
Apothecary. (2013). Rheumatoid arthritis. Atlantic
Apothecary. Retrieved from http://www.atlanticapothecary.com/disease-state-management/arthritis/rheumatoid-arthritis/.
Cedars-Sinai.
(2013). Arthritis- Rheumatoid arthritis, osteoarthritis and spinal arthritis. Cedars-Sinai. Retrieved from http://www.cedars-sinai.edu/Patients/Health-Conditions/Arthritis---Rheumatoid-Arthritis-Osteoarthritis-and-Spinal-Arthritis.aspx.
Nutrition
Remarks (2013). Fish oil can reduce rheumatoid arthritis. Nutrition Remarks. Retrieved from http://www.nutritionremarks.com/2013/03/09/fish-oil-can-reduce-rheumatoid-arthritis-flu/.
Peterson, D.
(2012). Am I Th1 or Th2 or Th17? Living
Wellness. Retrieved from http://livingwellnessblog.wordpress.com/2012/10/12/am-i-th1-or-th2-or-th17/.
Rheumatologist.
(2011). Biologic drugs. Rheumatologist.
Retrieved from http://www.rheumatologysa.com/biologics.html.
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