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The Pathogenesis of

Rheumatoid Arthritis
Prof. Mohammed K. Senna
Abbreviations

M Macrophages
FBLs Fibroblasts
RA Rheumatoid arthritis
PMNLs Polymorphonuclear leukocytes
DC Dendritic cells
The etiology and pathogenesis of RA

• The etiology and pathogenesis of RA are


complex and multifaceted.
• A variety of predetermined genes and random
events and environmental factors contribute
to susceptibility and pathogenesis.
The etiology and pathogenesis of RA

As an introduction, a summary of how these mechanisms interact to create and


perpetuate RA is shown in the figure.
Role of Genes

• The initiation of RA begins years before the onset


of clinical symptoms.
• The earliest phases are marked by repeated
activation of innate immunity.

Repeated activation of innate immunity.

In susceptible subject In normal subject

This process involves certain specific


Self-limiting
genes that can help break tolerance and
lead to auto-reactivity
Role of Genes

Evidence for role of genes

RA concordance rate RA concordance rate 10% of patients with RA


monozygotic twins is 30% dizygotic twins is 5% have an affected 1st-degree
relative
Role of Genes

The risk gene

• The class II MHC allele DRβ1∗0401 (old name: HLA-DR4) is the


major genetic risk factors for RA.

• 70% of patients with RA express HLA-DR4 compared with 28%


of controls.

• This association is particularly strong for individuals who


develop RA associated with antibodies to CCP.
Role of Genes

The risk gene


This gene is associated with RA in some races but not all:

Race Risk gene


Spanish and Italian patients DRβ1∗1001 HLADR10
Chileans DRβ1∗0901 HLA-DR9
Arabs DRβ1∗0301 HLA-DR3
Asian Indians DRβ1∗0101 HLA-DR1
Israeli Jews DRβ1∗0101 HLA-DR1
Yakima Indians of North America DRβ1∗0101 HLA-DR1
Role of Genes

Protective Genes ????

Certain HLA-DR alleles, may


protect against the development
of RA in that they tend to be
HLA-DR5 (DRβ1∗1101)
found at lower frequency in RA HLA-DR2 (DRβ1∗1501)
HLA-DR3 (DRβ1∗0301)
patients than in controls HLA-DR7 (DRβ1∗0701)
Role of Genes

What is QKRAA? Shared epitope ??

This 5 amino acid motif (from70 to 74), when expressed in


the third HVR of HLA-DRB1, is known to carry susceptibility to
develop RA.

Q K R A A
glutamine leucine arginine alanine alanine
Role of Genes

What is QKRAA? Shared epitope ??


Genes-Environmental Interaction

Smoking

• The interaction between HLA-DR and


tobacco exposure is the best example of how
genes and the environment enhance risk.
• History of smoking in individual with SE
increases OR of developing RA by 40-fold.
• The extent of smoking is also predictive, with
the greatest risk seen with 20 pack-years.
The risk declines slowly with cessation of
smoking, taking more than a decade to begin
approaching nonsmokers.
Genes-Environmental Interaction

Smoking

Proposed Mechanisms

Repeated smoking Smoking

Repeated activation of innate


increase protein citrullination
immunity

auto-reactivity increased ability of SE-containing


in an individual with underlying HLA-DR molecules to bind
genetically predisposition citrullinated proteins
Genes-Environmental Interaction

Infection

• It is suggested that RA may result in Possible causative agents


response to an infectious agent in a
genetically susceptible host. Mycoplasma
• Because of the worldwide distribution Epstein-Barr virus (EBV)
of RA, it is hypothesized that an Cytomegalovirus
infectious agent must be universal. Parvovirus
Rubella virus.
Multistep Progression to the Development of Rheumatoid Arthritis
Multistep Progression to the Development of Rheumatoid Arthritis
Synovial Immunologic Processes and Inflammation of

Early RA
Early RA
Early RA T cell activation Inflammation/destruction
Early RA
Early RA
The earliest lesions in rheumatoid synovitis are

A) Micro-vascular injury

• with perivascular infiltration with


mononuclear cells.
• Before the onset of clinical symptoms,
the perivascular infiltrate is
predominantly composed of myeloid
cells, whereas in symptomatic arthritis, T
cells predominate.
Early RA
Early RA
The earliest lesions in rheumatoid synovitis are

B) Synovial cells proliferation

• An increased number of synovial lining


cells.
• As the process continues, the synovium
becomes edematous and protrudes into
the joint cavity as villous projections.
Synovial Immunologic Processes and Inflammation of

Advanced RA
Synovial Immunologic Processes and Inflammation of Advanced Synovium

Rheumatoid Synovium
Rheumatoid Synovium

Characteristic Features Focal vascular changes


(microvascular injury,
thrombosis, and
Cellular Infiltration collected neovascularization)
into aggregates around small
blood vessels (Rheumatoid
synovial endothelial cells
express increased amounts of
adhesion molecules to
facilitate entry of cells into
tissue).

Hyperplasia and
hypertrophy of the
synovial lining cells
Edema
Synovial Immunologic Processes and Inflammation of advanced synovium

Cells
Cells T cells

The predominant infiltrating cell in RA synovium is the T lymphocyte

CD4+ T cells CD8+ T cells

form the majority of T cells in RA Form minority of T cells in RA


synovium, and are frequently synovium. Scattered throughout
found in close proximity to HLA- the tissue.
DR+ M and DCs.
Cells T cells

Evidence for that inflammatory process in RA is driven by the CD4+ T cells:


• The predominance of CD4+ T cells in the synovium.
• The increase in sIL-2R (a product of activated T cells).
• Amelioration of RA by:
o Removal of T cells (by thoracic duct drainage or peripheral lymphapheresis)
o Suppression of T cell proliferation or function by drugs (e.g. cyclosporine,
leflunomide, or nondepleting monoclonal antibodies to CD4).
o Inhibitors of T cell activation (e.g. the T cell co-stimulation competitor, CTLA-
4·Ig (abatacept)).
• The association of RA with certain HLA-DR alleles, whose only known function is to
shape the repertoire of CD4+ T cells during ontogeny in the thymus and bind and
present antigenic peptides to CD4+ T cells in the periphery.
Cells B cells

Rheumatoid synovitis is also infiltrated by B


cells and antibody-producing plasma cells.
Within the synvoium, these cells generate

Polyclonal Ig RF Anti-bodies to CCP

which leads to local formation of immune complexes, hence


contribute to RA synovitis.
Cells B cells

Evidence for the contribution of B cells to the chronic inflammatory process:

Treatment with rituximab


(a monoclonal antibody to the B cell marker, CD20)

Prompt depletion of B cells

Partial amelioration of
A decline in serum RF
signs and symptoms of
titers
inflammation
Cells Mast Cells

• Increased numbers of activated mast cells in the rheumatoid synovium.


• Local release of the contents of their granules may contribute to inflammation.
Cells Fibroblasts (FBLs)

• The synovial FBLs in RA are activated.


• These activated FBLs are particularly
prominent at the interface with bone
and cartilage.
• They produce enzymes (e.g. collagenase
and cathepsins) that can degrade
components of the articular matrix.
Cells Fibroblasts (FBLs)

FBLS play a critical part in many pathogenic events in the RA synovium. They can contribute to
pathology through a reduced ability to undergo apoptosis (forming pannus), the production of
proteases that degrade the extracellular matrix, and invasion into cartilage. In addition, FBLS
produce a variety of molecules that modulate growth, inflammation, angiogenesis, and cell
recruitment, and induce activation of and cytokine production by immune cells.
Cells Osteoclasts

Osteoclasts are also prominent at sites of bone erosion


Synovial Immunologic Processes and Inflammation of advanced synovium

Cytokines
Cytokines Pro-inflammatory Cytokines

The RA synovium is characterized by the presence of a number of cytokines


(secreted products of activated lymphocytes, M, and FBLs.

These cytokines account for many pathologic and clinical


manifestations of RA including

The synovial tissue Synovial Cartilage and bone The systemic


manifestations of
inflammation proliferation damage RA
Cytokines Pro-inflammatory Cytokines

Within the rheumatoid synovium, CD4+ T cells differentiate into TH1- cells
producing the pro-inflammatory IFN-γ and appear to be deficient in differentiation
into TH2-like cells capable of producing the anti-inflammatory cytokine IL-4:

T cells produce cytokines that


The ongoing secretion of IFN-γ in promote B cell proliferation and
absence of IL-4, activates M to differentiation into antibody-
produce the pro-inflammatory forming cells. The resultant
cytokines IL-1 and TNF and increase production of Ig, RF and antibodies
expression of HLA molecules. to CCP can lead to immune-complex
formation.
Cytokines Inhibitors of Cytokines Action

• In addition to the production of pro-inflammatory molecules, anti-


inflammatory (that tend to slow the inflammation) are also
produced:
• e.g. TGF-β which inhibits many of the features of rheumatoid
synovitis:
1. T cell activation and proliferation
2. B cell differentiation
3. Migration of cells into the inflammatory site
4. Generating a population of regulatory T cells, as a means to
control inflammation.
Synovial Immunologic Processes and Inflammation of advanced synovium

Synovial Fluid
Synovial Fluid

The exudative synovial fluid contains more PMNLs than mononuclear cells.

Mechanisms that stimulate the exudation of synovial fluid:

• Local production of cytokines, and products of complement activation enhance

migration of PMNLs into the synovial site.

• Vasoactive mediators (e.g. histamine produced by the mast cells) facilitate the

exudation of inflammatory cells into the synovial fluid.

• Vasodilatory effects of locally produced PG-E2 facilitate entry of inflammatory

cells into the inflammatory site.


Synovial Fluid

Once in the synovial fluid, the PMNLs ingest immune complexes, with the resultant:

• Production of reactive O2 metabolites and other inflammatory mediators,

further adding to the inflammatory process.

• Production of large amounts of COX and LOX pathway products by cells in the

synovial fluid and tissue further accentuates the signs and symptoms of

inflammation.
Synovial Immunologic Processes and Inflammation of advanced synovium

Bone and Cartilage Destruction


Pannus

Inflamed Synovium
PANNUS

Pannus is a vascular granulation tissue is composed of

Small blood
Proliferating Inflammatory
vessels
FBLs cells
(angiogenesis)

Pannus spreads to cover the articular cartilage

The destruction occurs in juxtaposition to the pauuns


Pannus
Pannus
When stimulated by IL-1 and TNF,
PANNUS CELLS

Produce a large amount Activate chondrocytes Activate osteoclasts


of degradative enzymes in situ
e.g. collagenase, stromelysin

Facilitate tissue Chondrocytes produce Local demineralization


damage proteolytic enzymes of bone

Local cartilage Inhibit synthesis of new


degradation matrix molecules
RA pathogenesis

Systemic Manifestations
Synovial Fluid

Systemic manifestations of RA can be accounted for by release of inflammatory


effector molecules from the synovium. These include IL-1,TNF, and IL-6, which
account for many of the manifestations of active RA, including malaise, fatigue, and
elevated levels of serum acute-phase reactants.
The importance of TNF in producing these manifestations is emphasized by the
prompt amelioration of symptoms following administration of a monoclonal
antibody to TNF or a soluble TNF receptor. This is associated with a decrease in
production of other pro-inflammatory cytokines, including IL-1 and IL-6.
In addition, immune complexes produced within the synovium and entering the
circulation may account for other features of the disease, such as systemic
vasculitis.
Synovial Immunologic Processes
and Inflammation
• Synovitis occurs when leukocytes infiltrate the synovial
compartment.
• Leukocyte accumulation primarily reflects migration rather
than local proliferation.
• Cell migration is enabled by endothelial activation in synovial
microvessels, which increases the expression of adhesion
molecules and chemokines.
• Neoangiogenesis, which is induced by local hypoxic
conditions and cytokines, is characteristic features of early
and established synovitis.
Synovial Immunologic Processes
and Inflammation
Adaptive immune pathway

The synovium in RA contains abundant dendritic cells that


express cytokines (IL-12, 15, 18, and 23), HLA class II
molecules, and costimulatory molecules

that are necessary for T-cell activation and


antigen presentation
Synovial Immunologic Processes
and Inflammation
Adaptive immune pathway

Synovial T-cell oligoclonality

Suggest ongoing local antigen-specific, T-


cell–mediated B-cell help.
Synovial Immunologic Processes
and Inflammation
Adaptive immune pathway

• Although RA is considered to be a disease that is mediated


by type 1 helper T cells, attention has increasingly focused
on the role of Th17, a subset that produces interleukin-
17A, 17F and TNF-α).
• Macrophage-derived and dendritic-cell–derived TGF-β and
IL- 1β, supports Th17 differentiation and suppresses
differentiation of regulatory T cells, thus shifting T-cell
homeostasis toward inflammation.
Synovial Immunologic Processes
and Inflammation
Adaptive immune pathway

• Interleukin-17A, which synergizes with TNF-α to promote


activation of fibroblasts and chondrocytes.
• Regulatory T cells that are detected in RA tissues have
limited functional capability. This imbalance between
Th17 and regulatory T cells may also reflect local TNF-α,
which blocks the activity of regulatory T cells.
Synovial Immunologic Processes
and Inflammation
Adaptive immune pathway

• Synovial B cells expansion and are mainly localized in T-


cell–B-cell aggregates.

• Plasmablasts and plasma cells are more widely distributed


in the synovium and also in juxta-articular bone marrow.
Adaptive and Innate
Immune Processes
within the Joint in
Rheumatoid Arthritis.
Synovial Immunologic Processes
and Inflammation
Innate immune pathway

Macrophages
• Central effectors of synovitis.
• Clinically effective biologic agents consistently reduce
macrophage infiltration in the synovium.
• Act through release of cytokines (e.g., TNF-α and IL-1, 6,
12, 15, 18, and 23), ROS, nitrogen intermediates,
production of prostanoids and matrix-degrading enzymes,
phagocytosis, and antigen presentation.
Synovial Immunologic Processes
and Inflammation
Innate immune pathway

Neutrophils
• Contribute to synovitis by synthesizing prostaglandins,
proteases, and ROS.

Mast cells
• Produce high levels of vasoactive amines, cytokines,
chemokines, and proteases.
Synovial Immunologic Processes
and Inflammation
Cytokines and Intracellular Signaling Pathways

TNF-α
• Plays a fundamental role through activation of cytokine
and chemokine expression, expression of endothelial-cell
AM, protection of synovial fibroblasts, promotion of
angiogenesis, suppression of regulatory T cells, and
induction of pain
Synovial Immunologic Processes
and Inflammation
Cytokines and Intracellular Signaling Pathways

IL-6
• Local leukocyte activation
• Autoantibody production
• Promote acute phase responses
• Anemia
• Cognitive dysfunction
• Lipid-metabolism dysregulation.
Synovial Immunologic Processes
and Inflammation
Cytokines and Intracellular Signaling Pathways

IL-1 family
• IL-1α, 1β, 18, and 33
• Abundantly expressed in RA
• They promote activation of leukocytes, endothelial cells,
chondrocytes, and osteoclasts.
Synovial Immunologic Processes
and Inflammation
Mesenchymal Tissue Responses

Synovial hyperplasia
Due to altered resistance to apoptosis, which is mediated by
diverse pathways, including:
• Mutations of the tumor-suppressor gene p5363;
• Expression of stress proteins (e.g., heat-shock protein 70),
which foster the survival of FLSs
• Modulation of the function of the endoplasmatic
reticulum by synoviolin, that regulates the balance of cell
proliferation and apoptosis.
Structural Damage
Structur al Damage
Cartilage Damage

• Hyperplastic synovium is the major contributor to


cartilage damage in RA.
• Loss of the normally protective effects of synovium (e.g.,
reduced expression of lubricin) alter the protein-binding
characteristics of the cartilage surface, promoting FLS
adhesion and invasion.
• FLS synthesis of MMPs, promotes degrade type II collagen
network, a process that alters GAC content and water
retention and leads directly to biomechanical dysfunction.
• Other matrix enzymes (e.g., ADAMTS 5) degrade aggrecan
and thus further diminish cartilage integrity.
Structural Damage
Cartilage Damage

• Endogenous enzyme inhibitors, such as TIMPs, fail to


reverse this destructive cascade.
• Moreover, articular cartilage itself has limited regenerative
potential.
Structur al Damage
Bone Erosion

• Occurs rapidly (affecting 80% of patients within 1 year


after diagnosis71)
• Associated with prolonged, increased inflammation.
Structur al Damage
Bone Erosion

RANKL
receptor activator of TNF-α
NF-κB ligand

MC-SF IL-1,6,17

Amplify osteoclast differentiation and activation


Structur al Damage
Bone Erosion

• Mechanical factors predispose particular sites to erosion.


• Thus, “mechanically vulnerable” sites such as the 2nd ; 3rd
MC prone to erosive changes.
Systemic Consequences
of RA
Systemic Consequences
of Rheumatoid Arthritis
• RA is associated with increased rates of
cardiovascular illness (mortality rate,=1.5),
including MI, cerebrovascular events, and
HF. Acute phase
reactants
immune complexes

• Not explained by traditional risk factors.altered


cytokines
(interleukin-6 and
lipid particles
TNF-α)

Increase endothelial activation and


render atheromatous plaques unstable.
Systemic Consequences
of Rheumatoid Arthritis
Inflammation in rheumatoid arthritis also
affects
• Brain (fatigue and reduced cognitive
function)
• Liver (elevated acute-phase response and
anemia of chronic disease)
• Lungs (inflammatory and fibrotic disease,
lung cancer)
• Exocrine glands (secondary SS)