What are the cellular and extracellular tissue factors in the pathophysiology of AA (inflammatory) amyloidosis?

Answer

Cellular and extracellular tissue factors :

Mononuclear phagocytes might play a role in degradation of SAA and initiation of development of AA amyloidosis.

Polymorphisms of the mannose-binding lectin 2(MBL-2) gene leading to decreased levels of functional MBL have been related to defective macrophage function. This suggests that genetic background may affect the ability of mononuclear phagocytes to effectively process and degrade SAA proteins.

Additional tissue factors, such as enzymes found in the extracellular matrix, are likely to be involved in the proteolytic processing of SAA. Matrix metalloproteinases (MMPs) are involved in generation of SAA N-terminal fragments. In vitro studies confirmed that human SAAs and AA amyloid fibrils are susceptible to proteolytic cleavage by MMPs, generating fragments of different sizes. Studies have demonstrated that susceptibility to MMP-1 degradation is highly dependent on SAA1 genotype.^[7]

The factors responsible for determining the site of deposition in any form of amyloidosis have not been identified. AA fibrils have been generated in tissue cultures by incubating SAA with macrophages. Deposits are frequently found in tissues with large numbers of phagocytic cells, notably the liver and spleen, but other affected organs, such as the kidneys, do not have the same cellular composition. Some data, derived from analysis of renal biopsy specimens, have suggested that glycoxidative modification of proteins, probably the AA protein itself, may also play a role in AA deposition in kidneys.

Did this answer your question?

Yes No

Additional feedback? (Optional)

Thank you for your feedback!

Pinney JH, Lachmann HJ. Systemic AA Amyloidosis. Subcell Biochem. 2012. 65:541-64. [Medline].
Ogawa S, Murakami T, Inoshima Y, Ishiguro N. Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis. Amyloid. 2015 Nov 20. 1-8. [Medline].
Perfetto F, Moggi-Pignone A, Livi R, Tempestini A, Bergesio F, Matucci-Cerinic M. Systemic amyloidosis: a challenge for the rheumatologist. Nat Rev Rheumatol. 2010 Jul. 6(7):417-29. [Medline].
Lane T, Gillmore JD, Wechalekar AD, Hawkins PN, Lachmann HJ. Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature. Clin Exp Rheumatol. 2015 Nov-Dec. 33 (6 Suppl 94):46-53. [Medline].
Obici L, Raimondi S, Lavatelli F, Bellotti V, Merlini G. Susceptibility to AA amyloidosis in rheumatic diseases: a critical overview. Arthritis Rheum. 2009 Oct 15. 61(10):1435-40. [Medline].
Sipe J. Revised nomenclature for serum amyloid A (SAA). Nomenclature Committee of the International Society of Amyloidosis. Part 2. Amyloid. 1999 Mar. 6(1):67-70. [Medline].
van der Hilst JC, Yamada T, Op den Camp HJ, van der Meer JW, Drenth JP, Simon A. Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis. Rheumatology (Oxford). 2008 Nov. 47(11):1651-4. [Medline].
Brunger AF, Nienhuis HLA, Bijzet J, Hazenberg BPC. Causes of AA amyloidosis: a systematic review. Amyloid. 2020 Mar. 27 (1):1-12. [Medline].
Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007 Jun 7. 356(23):2361-71. [Medline].
Silva L, Sampaio L, Terroso G, Almeida G, Lucas R, Rios E, et al. Amyloidosis secondary to rheumatic diseases - 16 cases. Acta Reumatol Port. 2010 Oct-Dec. 35(5):518-23. [Medline].
Wester AL, Vatn MH, Fausa O. Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998. Inflamm Bowel Dis. 2001 Nov. 7(4):295-300. [Medline].
Lejmi H, Jen KY, Olson JL, James SH, Sam R. Characteristics of AA amyloidosis patients in San Francisco. Nephrology (Carlton). 2016 Apr. 21 (4):308-13. [Medline].
Bernabei L, Waxman A, Caponetti G, Fajgenbaum DC, Weiss BM. AA amyloidosis associated with Castleman disease: A case report and review of the literature. Medicine (Baltimore). 2020 Feb. 99 (6):e18978. [Medline]. [Full Text].
Beloncle F, Sayegh J, Eymerit-Morin C, Duveau A, Augusto JF. AA amyloidosis as a complication of primary lymphedema. Amyloid. 2013 Aug 21. [Medline].
Lee H, Han KH, Jung YH, Kang HG, Moon KC, Ha IS, et al. A case of systemic amyloidosis associated with cyclic neutropenia. Pediatr Nephrol. 2011 Apr. 26(4):625-9. [Medline].
Simms RW, Prout MN, Cohen AS. The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol. 1994 Aug. 8(3):627-34. [Medline].
Kuroda T, Tanabe N, Nozawa Y, Sato H, Nakatsue T, Kobayashi D, et al. Effects of Biologic Agents in Patients with Rheumatoid Arthritis and Amyloidosis Treated with Hemodialysis. Intern Med. 2016. 55 (19):2777-2783. [Medline]. [Full Text].
Yildirim Cetin G, Ganiyusufoglu E, Solmaz D, Cagatay Y, Yılmaz Oner S, Erer B, et al. The rate and significance of type 1/type 2 serum amyloid A protein gene polymorphisms in patients with ankylosing spondylitis and amyloidosis. Amyloid. 2015. 22 (3):207-8. [Medline].
Booth DR, Booth SE, Gillmore JD, et al. SAA1 alleles as risk factors in reactive systemic AA amyloidosis. Amyloid. 1998 Dec. 5(4):262-5. [Medline].
Joss N, McLaughlin K, Simpson K, et al. Presentation, survival and prognostic markers in AA amyloidosis. QJM. 2000 Aug. 93(8):535-42. [Medline].
Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007 Jun 7. 356(23):2361-71. [Medline].
Myllykangas-Luosujärvi R, Aho K, Kautiainen H, Hakala M. Amyloidosis in a nationwide series of 1666 subjects with rheumatoid arthritis who died during 1989 in Finland. Rheumatology (Oxford). 1999 Jun. 38(6):499-503. [Medline].
Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001 Jul 7. 358(9275):24-9. [Medline].
Immonen K, Finne P, Hakala M, Kautiainen H, Pettersson T, Grönhagen-Riska C. No improvement in survival of patients with amyloidosis associated with inflammatory rheumatic diseases -- data from the Finnish national registry for kidney diseases. J Rheumatol. 2008 Jul. 35(7):1334-8. [Medline].
Tanaka F, Migita K, Honda S, Fukuda T, Mine M, Nakamura T, et al. Clinical outcome and survival of secondary (AA) amyloidosis. Clin Exp Rheumatol. 2003 May-Jun. 21(3):343-6. [Medline].
Uda H, Yokota A, Kobayashi K, Miyake T, Fushimi H, Maeda A, et al. Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis. J Rheumatol. 2006 Aug. 33(8):1482-7. [Medline].
Enríquez R, Sirvent AE, Padilla S, Noguera-Pons R, Andrada E, Ardoy F, et al. Nephrotic syndrome and AA amyloidosis revealing adult-onset cryopyrin-associated periodic syndrome. Ren Fail. 2013. 35(5):738-41. [Medline].
Sattianayagam PT, Gillmore JD, Pinney JH, Gibbs SD, Wechalekar AD, Gilbertson JA, et al. Inflammatory bowel disease and systemic AA amyloidosis. Dig Dis Sci. 2013 Jun. 58(6):1689-97. [Medline].
Papathanasiou M, Carpinteiro A, Rischpler C, Hagenacker T, Rassaf T, Luedike P. Diagnosing cardiac amyloidosis in every-day practice: A practical guide for the cardiologist. Int J Cardiol Heart Vasc. 2020 Jun. 28:100519. [Medline]. [Full Text].
Wall JS, Williams A, Richey T, Stuckey A, Huang Y, Wooliver C, et al. A binding-site barrier affects imaging efficiency of high affinity amyloid-reactive peptide radiotracers in vivo. PLoS One. 2013. 8 (6):e66181. [Medline].
Picken MM. Amyloidosis-where are we now and where are we heading?. Arch Pathol Lab Med. 2010 Apr. 134(4):545-51. [Medline].
Livneh A, Zemer D, Langevitz P, et al. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum. 1994 Dec. 37(12):1804-11. [Medline].
Solak Y, Siriopol D, Yildiz A, Yilmaz MI, Ortiz A, Covic A, et al. Colchicine in Renal Medicine: New Virtues of an Ancient Friend. Blood Purif. 2017. 43 (1-3):125-135. [Medline]. [Full Text].
Ahlmen M, Ahlmen J, Svalander C, et al. Cytotoxic drug treatment of reactive amyloidosis in rheumatoid arthritis with special reference to renal insufficiency. Clin Rheumatol. 1987 Mar. 6(1):27-38. [Medline].
Fernández-Nebro A, Tomero E, Ortiz-Santamaría V, Castro MC, Olivé A, de Haro M, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists. Am J Med. 2005 May. 118(5):552-6. [Medline].
Leslie KS, Lachmann HJ, Bruning E, McGrath JA, Bybee A, Gallimore JR, et al. Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Arch Dermatol. 2006 Dec. 142(12):1591-7. [Medline].
Ugurlu S, Hacioglu A, Adibnia Y, Hamuryudan V, Ozdogan H. Tocilizumab in the treatment of twelve cases with aa amyloidosis secondary to familial mediterranean fever. Orphanet J Rare Dis. 2017 May 30. 12 (1):105. [Medline]. [Full Text].
Esatoglu SN, Hatemi G, Ugurlu S, Gokturk A, Tascilar K, Ozdogan H. Long-term follow-up of secondary amyloidosis patients treated with tumor necrosis factor inhibitor therapy: A STROBE-compliant observational study. Medicine (Baltimore). 2017 Aug. 96 (34):e7859. [Medline]. [Full Text].
Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010 Nov 4. 468(7320):93-7. [Medline]. [Full Text].
Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep 17. 373 (12):1106-14. [Medline].
Dember LM, Hawkins PN, Hazenberg BP, Gorevic PD, Merlini G, Butrimiene I, et al. Eprodisate for the treatment of renal disease in AA amyloidosis. N Engl J Med. 2007 Jun 7. 356(23):2349-60. [Medline].
Bellus Health: Phase 3 Results of Kiacta for AA Amyloidosis. Drug Discovery & Development. Available at https://www.drugdiscoverytrends.com/bellus-health-phase-3-results-of-kiacta-for-aa-amyloidosis/. June 30, 2016; Accessed: August 11, 2020.
Vandecasteele SJ, De Paepe P, De Vriese AS. Successful treatment of renal AA amyloidosis in familial Mediterranean fever with pegylated alpha-2a interferon. Clin Nephrol. 2011 Feb. 75 Suppl 1:1-3. [Medline].
Green H, Lichtenberg S, Rahamimov R, Livneh A, Chagnac A, Mor E, et al. Familial Mediterranean Fever Is Associated With Increased Mortality After Kidney Transplantation-A 19 Years' Single Center Experience. Transplantation. 2017 Oct. 101 (10):2621-2626. [Medline].
Altindal M, Turkmen E, Yildirim T, Yilmaz R, Aki FT, Arici M, et al. Kidney transplantation for end-stage renal disease secondary to familial Mediterranean fever. Clin Transplant. 2016 Jul. 30 (7):787-90. [Medline].
Tatar E, Karatas M, Aykas A, Okut G, Bozkaya G, Uslu A. Infections After Renal Transplant in Recipients With Familial Mediterranean Fever: A Life-Threatening Issue. Exp Clin Transplant. 2017 Feb. 15 (Suppl 1):240-243. [Medline]. [Full Text].
Kofman T, Grimbert P, Poitrine FC, Zuber J, Garrigue V, Mousson C, et al. Renal Transplantation in Patients With AA Amyloidosis Nephropathy: Results From a French Multicenter Study. Am J Transplant. 2011 Jun 30. [Medline].
Kuroda T, Otaki Y, Sato H, Fujimura T, Nakatsue T, Murakami S, et al. A case of AA amyloidosis associated with rheumatoid arthritis effectively treated with Infliximab. Rheumatol Int. 2008 Sep. 28(11):1155-9. [Medline].
Shimoyama M, Ohtahara A, Fukui H, Okamura T, Shimizu H, Miyamoto M, et al. Acute secondary gastrointestinal amyloidosis in a patient with rheumatoid arthritis. Am J Med Sci. 2003 Sep. 326(3):145-7. [Medline].
Fushimi T, Takahashi Y, Kashima Y, et al. Severe protein losing enteropathy with intractable diarrhea due to systemic AA amyloidosis, successfully treated with corticosteroid and octreotide. Amyloid. 2005 Mar. 12(1):48-53. [Medline].

Media Gallery

of 0

Author

Richa Dhawan, MD, CCD Associate Professor, Director of Osteoporosis Clinic, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport

Richa Dhawan, MD, CCD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, American Association of Physicians of Indian Origin

Disclosure: Nothing to disclose.

Coauthor(s)

Mohammed Mubashir Ahmed, MD Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine

Mohammed Mubashir Ahmed, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Federation for Medical Research

Disclosure: Nothing to disclose.

Eisha Mubashir, MD Fellow in Rheumatology, Department of Medicine, Center of Excellence for Arthritis and Rheumatology, Louisiana State University School of Medicine in Shreveport

Disclosure: Nothing to disclose.

Ratinder J Kaur, MD Fellow, Department of Rheumatology, Louisiana State University School of Medicine in Shreveport

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Lewis Katz School of Medicine at Temple University

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University School of Medicine in Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Affairs Medical Center

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Joel N Buxbaum, MD Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute

Joel N Buxbaum, MD is a member of the following medical societies: American Association for the Advancement of Science, American Society for Clinical Investigation, American Society of Human Genetics, Association of American Physicians, Association of Black Cardiologists, Henry Kunkel Society

Disclosure: Received consulting fee from Foldrx pharmaceuticals for consulting; Received consulting fee from Isis pharmaceuticals for consulting; Received consulting fee from alnylam pharmaceutical for consulting; Received consulting fee from Pfizer Pharmaceuticals for consulting.

What are the cellular and extracellular tissue factors in the pathophysiology of AA (inflammatory) amyloidosis?

Related Questions:

References

Tables

Contributor Information and Disclosures