Rheumatoid arthritis pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
The | [[Rheumatoid arthritis]] is mediated by the combination of a predisposing [[genotype]] along with which [[genetic]] factors, [[Environmental Lung Diseases|environmental]] factors, and [[Microorganisms|microorganisms]] contribute, resulting in the [[inflammation]] and destruction of the [[synovial membrane]]. These factors lead to [[citrullination]] or [[post-translational modifications]], resulting in the production of altered peptides. The altered [[peptides]] bind to [[MHC]] protein with shared [[epitopes]] which further leads to [[antigen]] presentation to [[T-cells]]. | ||
[[T-cells]] further stimulate [[B-cells]] and cytokines which results in cartilage damage. [[Mutation]] of [[human leukocyte antigen]] (HLA) genes on [[chromosome]] 6 is involved in pathogenesis of [[rheumatoid arthritis]]. Various conditions associated with [[RA]] include [[vasculitis]], [[uveitis]], [[scleritis]], peripheral [[ulcerative keratitis]], | |||
[[interstitial fibrosis]], pulmonary [[nodules]], [[bronchiolitis obliterans]], organizing [[pneumonia]], [[venous thromboembolism]], [[pericarditis]], [[myocarditis]], [[congestive heart failure]], [[atrial fibrillation]], [[sjogren's syndrome]], and [[felty's syndrome]]. | |||
==Pathophysiology== | |||
[[Rheumatoid arthritis]] is mediated by the combination of a predisposing [[genotype]] along with [[genetic]] factors, [[Environmental Lung Diseases|environmental]] factors, and [[Microorganisms|microorganisms]], resulting in the [[inflammation]] and destruction of the [[synovial membrane]]. | |||
[ | |||
'''Various factors involved are''': | |||
'''Environmental factors''': | |||
* Environmental factors lead to repeated activation of [[innate immunity]] at [[mucosal]] surfaces. | |||
*[[Smoking]] effects the [[genes]] to increase susceptibility up to 20 to 40 fold. | |||
**[[Smoking]] causes increased expression of peptidyl arginine deiminase (PAD) in [[alveolar]] [[macrophages]]. | |||
== | **Peptidyl arginine deiminase converts arginine to [[citrulline]], the process is known as [[citrullination]], in the airway which further creates neoantigens that can be recognized by the adaptive [[immune system]].<ref name="pmid19479873">{{cite journal |vauthors=Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L |title=Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important |journal=Arthritis Rheum. |volume=60 |issue=6 |pages=1597–603 |date=June 2009 |pmid=19479873 |pmc=2732897 |doi=10.1002/art.24572 |url=}}</ref><ref name="pmid18413445">{{cite journal |vauthors=Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI |title=Smoking increases peptidyl arginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells |journal=Ann. Rheum. Dis. |volume=67 |issue=10 |pages=1488–92 |date=October 2008 |pmid=18413445 |doi=10.1136/ard.2007.075192 |url=}}</ref> | ||
'''Genetic factors:''' | |||
*Genetics factors such as [[human leukocyte antigen]] (HLA)-DR. | |||
*These [[genes]] are involved in inducing [[immune response]], [[matrix]] regulation, and [[inflammation]].<ref name="pmid24072602">{{cite journal |vauthors=Bottini N, Firestein GS |title=Epigenetics in rheumatoid arthritis: a primer for rheumatologists |journal=Curr Rheumatol Rep |volume=15 |issue=11 |pages=372 |date=November 2013 |pmid=24072602 |doi=10.1007/s11926-013-0372-9 |url=}}</ref> | |||
'''Microrganisms:''' | |||
*In [[periodontal disease]], P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases. | |||
*This can lead to [[citrullination]] and thereby promotes anti-citrullinated protein antibodies (ACPA) | |||
*A. actinomycetemcomitans produces a [[toxin]] that increases [[calcium]] influx into [[neutrophils]] which further leads to [[citrullination]] of [[peptides]] and promotes APCA. | |||
===Pathogenesis=== | === '''Pathogenesis''' === | ||
[[ | *All the above factors lead to [[citrullination]] or [[post-translational modifications]]. | ||
*The altered [[peptides]] bind to [[MHC]] protein with shared [[epitopes]] which further leads to [[antigen]] presentation to [[T-cells]]. | |||
* | *[[T cells]] further stimulate [[B cells]] to produce a range of [[antibodies]] that recognize self-[[proteins]], including [[Rheumatoid factor|rheumatoid]] factors and anti-citrullinated protein antibodies (ACPAs). | ||
* | *[[Fibroblast]]-like synoviocytes, antigen presenting cells (APCs), and [[macrophages]] are activated locally and produce various [[inflammatory]] factors. | ||
*The [[autoimmune]] response causes [[synovial inflammation]] resulting in [[immune complex]] formation and [[complement]] activation, leading to an increase in [[cytokine]] production and [[synovial]] [[vascular]] leakage. | |||
*[[Cytokine|Cytokines]] lead to [[bone]] and [[cartilage]] destruction. | |||
* | |||
* | |||
* | |||
==Genetics== | ==Genetics== | ||
*[ | *The development of [[rheumatoid arthritis]] is the result of [[mutation]] of [[human leukocyte antigen]] (HLA) genes on [[chromosome]] 6.<ref name="pmid9608321">{{cite journal |vauthors=Reveille JD |title=The genetic contribution to the pathogenesis of rheumatoid arthritis |journal=Curr Opin Rheumatol |volume=10 |issue=3 |pages=187–200 |date=May 1998 |pmid=9608321 |doi= |url=}}</ref><ref name="pmid21176794">{{cite journal |vauthors=Entezami P, Fox DA, Clapham PJ, Chung KC |title=Historical perspective on the etiology of rheumatoid arthritis |journal=Hand Clin |volume=27 |issue=1 |pages=1–10 |date=February 2011 |pmid=21176794 |pmc=3119866 |doi=10.1016/j.hcl.2010.09.006 |url=}}</ref> | ||
==Associated Conditions== | ==Associated Conditions== | ||
Conditions associated with rheumatoid arthritis include:<ref name="pmid22527950">{{cite journal |vauthors=Deal C |title=Bone loss in rheumatoid arthritis: systemic, periarticular, and focal |journal=Curr Rheumatol Rep |volume=14 |issue=3 |pages=231–7 |date=June 2012 |pmid=22527950 |doi=10.1007/s11926-012-0253-7 |url=}}</ref><ref name="pmid6378209">{{cite journal |vauthors=Halla JT, Koopman WJ, Fallahi S, Oh SJ, Gay RE, Schrohenloher RE |title=Rheumatoid myositis. Clinical and histologic features and possible pathogenesis |journal=Arthritis Rheum. |volume=27 |issue=7 |pages=737–43 |date=July 1984 |pmid=6378209 |doi= |url=}}</ref> | |||
*[[Osteopenia]] | |||
*[[Myositis]] | |||
*[[Vasculitis]] | |||
*[[Uveitis]] | |||
*[[Scleritis]] | |||
*Peripheral [[ulcerative keratitis]] | |||
*[[Interstitial fibrosis]] | |||
*Pulmonary [[nodules]] | |||
*[[Bronchiolitis obliterans]] | |||
*Organizing [[pneumonia]] | |||
*[[Venous thromboembolism]] | |||
*[[Pericarditis]] | |||
*[[Myocarditis]] | |||
*[[Congestive heart failure]] | |||
*[[Atrial fibrillation]] | |||
*[[Sjogren's syndrome]] | |||
*[[Felty's syndrome]] | |||
==Gross Pathology== | ==Gross Pathology== | ||
On gross pathology of [[rheumatoid arthritis]] the following features may be noticed:<ref name="pmid404905">{{cite journal |vauthors=Resnick D, Niwayama G, Coutts RD |title=Subchondral cysts (geodes) in arthritic disorders: pathologic and radiographic appearance of the hip joint |journal=AJR Am J Roentgenol |volume=128 |issue=5 |pages=799–806 |date=May 1977 |pmid=404905 |doi=10.2214/ajr.128.5.799 |url=}}</ref> | |||
*Irregular surface, seen due to [[synovial]] hyperplasia. | |||
*Subchondral [[cysts]], usually present at the later stage of the disease. | |||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
On microscopic histopathological analysis:<ref name="pmid14532152">{{cite journal |vauthors=Koch AE |title=Angiogenesis as a target in rheumatoid arthritis |journal=Ann. Rheum. Dis. |volume=62 Suppl 2 |issue= |pages=ii60–7 |date=November 2003 |pmid=14532152 |pmc=1766740 |doi= |url=}}</ref><ref name="pmid9627005">{{cite journal |vauthors=Koch AE |title=Review: angiogenesis: implications for rheumatoid arthritis |journal=Arthritis Rheum. |volume=41 |issue=6 |pages=951–62 |date=June 1998 |pmid=9627005 |doi=10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D |url=}}</ref> | |||
*The earliest finding is the formation of the new synovial [[blood vessel|blood vessels]]. | |||
*Hypertrophy of [[synovial]] lining layer and infiltration of [[mononuclear cells]] may be observed. | |||
*Chronic [[inflammation]] with [[lymphocytic]] [[Infiltration (medical)|infiltration]] may be seen. | |||
*There is [[pannus]] formation which consists of fibrovascular tissue or [[Granulation tissue|granulation]] tissue. | |||
==References== | ==References== | ||
Latest revision as of 19:54, 23 April 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]
Overview
Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with which genetic factors, environmental factors, and microorganisms contribute, resulting in the inflammation and destruction of the synovial membrane. These factors lead to citrullination or post-translational modifications, resulting in the production of altered peptides. The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells. T-cells further stimulate B-cells and cytokines which results in cartilage damage. Mutation of human leukocyte antigen (HLA) genes on chromosome 6 is involved in pathogenesis of rheumatoid arthritis. Various conditions associated with RA include vasculitis, uveitis, scleritis, peripheral ulcerative keratitis, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, organizing pneumonia, venous thromboembolism, pericarditis, myocarditis, congestive heart failure, atrial fibrillation, sjogren's syndrome, and felty's syndrome.
Pathophysiology
Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with genetic factors, environmental factors, and microorganisms, resulting in the inflammation and destruction of the synovial membrane.
Various factors involved are:
Environmental factors:
- Environmental factors lead to repeated activation of innate immunity at mucosal surfaces.
- Smoking effects the genes to increase susceptibility up to 20 to 40 fold.
- Smoking causes increased expression of peptidyl arginine deiminase (PAD) in alveolar macrophages.
- Peptidyl arginine deiminase converts arginine to citrulline, the process is known as citrullination, in the airway which further creates neoantigens that can be recognized by the adaptive immune system.[1][2]
Genetic factors:
- Genetics factors such as human leukocyte antigen (HLA)-DR.
- These genes are involved in inducing immune response, matrix regulation, and inflammation.[3]
Microrganisms:
- In periodontal disease, P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
- This can lead to citrullination and thereby promotes anti-citrullinated protein antibodies (ACPA)
- A. actinomycetemcomitans produces a toxin that increases calcium influx into neutrophils which further leads to citrullination of peptides and promotes APCA.
Pathogenesis
- All the above factors lead to citrullination or post-translational modifications.
- The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells.
- T cells further stimulate B cells to produce a range of antibodies that recognize self-proteins, including rheumatoid factors and anti-citrullinated protein antibodies (ACPAs).
- Fibroblast-like synoviocytes, antigen presenting cells (APCs), and macrophages are activated locally and produce various inflammatory factors.
- The autoimmune response causes synovial inflammation resulting in immune complex formation and complement activation, leading to an increase in cytokine production and synovial vascular leakage.
- Cytokines lead to bone and cartilage destruction.
Genetics
- The development of rheumatoid arthritis is the result of mutation of human leukocyte antigen (HLA) genes on chromosome 6.[4][5]
Associated Conditions
Conditions associated with rheumatoid arthritis include:[6][7]
- Osteopenia
- Myositis
- Vasculitis
- Uveitis
- Scleritis
- Peripheral ulcerative keratitis
- Interstitial fibrosis
- Pulmonary nodules
- Bronchiolitis obliterans
- Organizing pneumonia
- Venous thromboembolism
- Pericarditis
- Myocarditis
- Congestive heart failure
- Atrial fibrillation
- Sjogren's syndrome
- Felty's syndrome
Gross Pathology
On gross pathology of rheumatoid arthritis the following features may be noticed:[8]
- Irregular surface, seen due to synovial hyperplasia.
- Subchondral cysts, usually present at the later stage of the disease.
Microscopic Pathology
On microscopic histopathological analysis:[9][10]
- The earliest finding is the formation of the new synovial blood vessels.
- Hypertrophy of synovial lining layer and infiltration of mononuclear cells may be observed.
- Chronic inflammation with lymphocytic infiltration may be seen.
- There is pannus formation which consists of fibrovascular tissue or granulation tissue.
References
- ↑ Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L (June 2009). "Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important". Arthritis Rheum. 60 (6): 1597–603. doi:10.1002/art.24572. PMC 2732897. PMID 19479873.
- ↑ Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI (October 2008). "Smoking increases peptidyl arginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells". Ann. Rheum. Dis. 67 (10): 1488–92. doi:10.1136/ard.2007.075192. PMID 18413445.
- ↑ Bottini N, Firestein GS (November 2013). "Epigenetics in rheumatoid arthritis: a primer for rheumatologists". Curr Rheumatol Rep. 15 (11): 372. doi:10.1007/s11926-013-0372-9. PMID 24072602.
- ↑ Reveille JD (May 1998). "The genetic contribution to the pathogenesis of rheumatoid arthritis". Curr Opin Rheumatol. 10 (3): 187–200. PMID 9608321.
- ↑ Entezami P, Fox DA, Clapham PJ, Chung KC (February 2011). "Historical perspective on the etiology of rheumatoid arthritis". Hand Clin. 27 (1): 1–10. doi:10.1016/j.hcl.2010.09.006. PMC 3119866. PMID 21176794.
- ↑ Deal C (June 2012). "Bone loss in rheumatoid arthritis: systemic, periarticular, and focal". Curr Rheumatol Rep. 14 (3): 231–7. doi:10.1007/s11926-012-0253-7. PMID 22527950.
- ↑ Halla JT, Koopman WJ, Fallahi S, Oh SJ, Gay RE, Schrohenloher RE (July 1984). "Rheumatoid myositis. Clinical and histologic features and possible pathogenesis". Arthritis Rheum. 27 (7): 737–43. PMID 6378209.
- ↑ Resnick D, Niwayama G, Coutts RD (May 1977). "Subchondral cysts (geodes) in arthritic disorders: pathologic and radiographic appearance of the hip joint". AJR Am J Roentgenol. 128 (5): 799–806. doi:10.2214/ajr.128.5.799. PMID 404905.
- ↑ Koch AE (November 2003). "Angiogenesis as a target in rheumatoid arthritis". Ann. Rheum. Dis. 62 Suppl 2: ii60–7. PMC 1766740. PMID 14532152.
- ↑ Koch AE (June 1998). "Review: angiogenesis: implications for rheumatoid arthritis". Arthritis Rheum. 41 (6): 951–62. doi:10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D. PMID 9627005.