Programmed cell death protein 1

Programmed cell death 1
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PDCD1 ; CD279; PD-1; PD1; SLEB2; hPD-1; hPD-l; hSLE1
External IDs OMIM: 600244 MGI: 104879 HomoloGene: 3681 GeneCards: PDCD1 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5133 18566
Ensembl ENSG00000188389 ENSMUSG00000026285
UniProt Q15116 Q02242
RefSeq (mRNA) NM_005018 NM_008798
RefSeq (protein) NP_005009 NP_032824
Location (UCSC) Chr 2:
241.85 – 241.86 Mb		 Chr 1:
94.04 – 94.05 Mb
PubMed search

Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein that in humans is encoded by the PDCD1 gene.[1][2] PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells.[2] PD-1 binds two ligands, PD-L1 and PD-L2.

PD-1, functioning as an immune checkpoint, plays an important role in down regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).[3][4]

A new class of drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used with varying success to treat some types of cancer.[5]

Structure

Programmed death 1 is a type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators.[6] The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals.[6][7] This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulates E3-ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation.[8] PD-1 is expressed on the surface of activated T cells, B cells, and macrophages,[9] suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.

Ligands

PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family.[10][11] PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney.[10][12] PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ.[13][14] PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.[11]

Function

Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively.[15][16] In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion.[10] Reduced T cell proliferation correlated with attenuated IL-2 secretion, which can be rescued by addition of cross-linking anti-CD28 antibodies or exogenous IL-2.[17]

Together, these data suggest that PD-1 negatively regulates T cell responses. Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4+ and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV model of chronic infection, Rafi Ahmed’s group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.[18]

As CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecule PD-1 has been independently explored as a target for immunotherapy. The 2C TCR recognizes the peptide SIYRYYGL in the context of H 2kb. 2C CD8 T cells incubated with IFN-γ treated B16 targets expressing SIYRYYGL peptide poorly lyse their targets and secrete low levels of IL-2.[14] However, PD-1 knockout 2C T cells have heightened cytolytic capacity and IL-2 secretion, suggesting that PD-1 negatively regulates anti-tumor CD8 T cell responses. Similarly, P815 mastocytoma, which does not express PD-L1 unless treated with IFN-γ, can be transduced to express PD-L1, resulting in inhibition of in vitro CD8-mediated cytotoxicity and enhanced in vivo tumor growth. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1[13][14] Together, these data suggest that expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy.[19] Said et al. showed that triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.[20]

Clinical significance

In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure. These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases.[2]

Cancer

PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. (PMID 26562159, PMID 26408403, PMID 24647569 , PMID 24217091 and PMID 23676558) Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer.[21] Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.

One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients.[22] Colon and pancreatic cancer did not have a response.

Nivolumab (Opdivo, Bristol-Myers Squibb), which also targets PD-1 receptors, was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.

Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects.It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015 Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.[23] Other drugs in early stage development targeting PD-1 receptors (aka checkpoint inhibitors): Pidilizumab (CT-011, Cure Tech), BMS 936559 (Bristol Myers Squibb), and Atezolizumab (MPDL3280A, Roche) which targets PD-L1.

HIV

Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (TIGIT), may augment immune responses and/or facilitate HIV eradication.[24][25]

Alzheimer's Disease

One recent study shows blocking PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice.[26]

References

  1. ↑ Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (Oct 1994). "Structure and chromosomal localization of the human PD-1 gene (PDCD1)". Genomics 23 (3): 704–6. doi:10.1006/geno.1994.1562. PMID 7851902.
  2. 1 2 3 "Entrez Gene: PDCD1 programmed cell death 1".
  3. ↑ Francisco LM, Sage PT, Sharpe AH (Jul 2010). "The PD-1 pathway in tolerance and autoimmunity". Immunological Reviews 236: 219–42. doi:10.1111/j.1600-065X.2010.00923.x. PMC 2919275. PMID 20636820.
  4. ↑ Fife BT, Pauken KE (Jan 2011). "The role of the PD-1 pathway in autoimmunity and peripheral tolerance". Annals of the New York Academy of Sciences 1217: 45–59. doi:10.1111/j.1749-6632.2010.05919.x. PMID 21276005.
  5. ↑ Loftus, Peter (16 Nov 2014). "New Bristol-Myers Drug Helped Skin-Cancer Patients in Trial Live Longer". Retrieved 24 Nov 2014.
  6. 1 2 Ishida Y, Agata Y, Shibahara K, Honjo T (Nov 1992). "Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death". The EMBO Journal 11 (11): 3887–95. PMC 556898. PMID 1396582.
  7. ↑ Blank C, Mackensen A (May 2007). "Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion". Cancer Immunology, Immunotherapy 56 (5): 739–45. doi:10.1007/s00262-006-0272-1. PMID 17195077.
  8. ↑ Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (August 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine 3 (10): 581–92. doi:10.1002/emmm.201100165. PMC 3191120. PMID 21739608.
  9. ↑ Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (May 1996). "Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes". International Immunology 8 (5): 765–72. doi:10.1093/intimm/8.5.765. PMID 8671665.
  10. 1 2 3 Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (Oct 2000). "Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation". The Journal of Experimental Medicine 192 (7): 1027–34. doi:10.1084/jem.192.7.1027. PMC 2193311. PMID 11015443.
  11. 1 2 Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (Mar 2001). "PD-L2 is a second ligand for PD-1 and inhibits T cell activation". Nature Immunology 2 (3): 261–8. doi:10.1038/85330. PMID 11224527.
  12. ↑ Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H (Nov 2002). "Expression of programmed death 1 ligands by murine T cells and APC". Journal of Immunology 169 (10): 5538–45. doi:10.4049/jimmunol.169.10.5538. PMID 12421930.
  13. 1 2 Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (Sep 2002). "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade". Proceedings of the National Academy of Sciences of the United States of America 99 (19): 12293–7. doi:10.1073/pnas.192461099. PMC 129438. PMID 12218188.
  14. 1 2 3 Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF (Feb 2004). "PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells". Cancer Research 64 (3): 1140–5. doi:10.1158/0008-5472.CAN-03-3259. PMID 14871849.
  15. ↑ Nishimura H, Nose M, Hiai H, Minato N, Honjo T (Aug 1999). "Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor". Immunity 11 (2): 141–51. doi:10.1016/S1074-7613(00)80089-8. PMID 10485649.
  16. ↑ Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (Jan 2001). "Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice". Science 291 (5502): 319–22. doi:10.1126/science.291.5502.319. PMID 11209085.
  17. ↑ Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM (Mar 2002). "PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2". European Journal of Immunology 32 (3): 634–43. doi:10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. PMID 11857337.
  18. ↑ Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (Feb 2006). "Restoring function in exhausted CD8 T cells during chronic viral infection". Nature 439 (7077): 682–7. doi:10.1038/nature04444. PMID 16382236.
  19. ↑ Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y (Apr 2005). "Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer". Clinical Cancer Research 11 (8): 2947–53. doi:10.1158/1078-0432.CCR-04-1469. PMID 15837746.
  20. ↑ Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP (Apr 2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nature Medicine 16 (4): 452–9. doi:10.1038/nm.2106. PMC 4229134. PMID 20208540.
  21. ↑ Weber J (Oct 2010). "Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade". Seminars in Oncology 37 (5): 430–9. doi:10.1053/j.seminoncol.2010.09.005. PMID 21074057.
  22. ↑ Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (Jun 2012). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer". The New England Journal of Medicine 366 (26): 2443–54. doi:10.1056/NEJMoa1200690. PMC 3544539. PMID 22658127. Lay summary – New York Times.
  23. ↑ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm
  24. ↑ Porichis F, Kaufmann DE (Mar 2012). "Role of PD-1 in HIV pathogenesis and as target for therapy". Current HIV/AIDS Reports 9 (1): 81–90. doi:10.1007/s11904-011-0106-4. PMC 3731769. PMID 22198819.
  25. ↑ Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS, et al. (Jan 2016). "TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection". PLoS Pathogens. doi:10.1371/journal.ppat.1005349. PMID 26741490.
  26. ↑ Baruch, Kuti; Deczkowska, Aleksandra; Rosenzweig, Neta; Tsitsou-Kampeli, Afroditi; Sharif, Alaa Mohammad; Matcovitch-Natan, Orit; Kertser, Alexander; David, Eyal; Amit, Ido (2016-02-01). "PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease". Nature Medicine 22 (2): 135–137. doi:10.1038/nm.4022. ISSN 1078-8956.

Further reading

  • Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR (Apr 1997). "Activation-induced expression of human programmed death-1 gene in T-lymphocytes". Experimental Cell Research 232 (1): 25–8. doi:10.1006/excr.1997.3493. PMID 9141617. 
  • Finger LR, Pu J, Wasserman R, Vibhakar R, Louie E, Hardy RR, Burrows PD, Billips LG (Sep 1997). "The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors". Gene 197 (1-2): 177–87. doi:10.1016/S0378-1119(97)00260-6. PMID 9332365. 
  • Iwai Y, Okazaki T, Nishimura H, Kawasaki A, Yagita H, Honjo T (Oct 2002). "Microanatomical localization of PD-1 in human tonsils". Immunology Letters 83 (3): 215–20. doi:10.1016/S0165-2478(02)00088-3. PMID 12095712. 
  • Prokunina L, Castillejo-López C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdóttir H, Gröndal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jönssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcón-Segovia D, Steinsson K, Alarcón-Riquelme ME (Dec 2002). "A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans". Nature Genetics 32 (4): 666–9. doi:10.1038/ng1020. PMID 12402038. 
  • Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, Khan N, Veldman G, Jacobs KA, Valge-Archer VE, Collins M, Carreno BM (Jan 2003). "Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses". Journal of Immunology 170 (2): 711–8. doi:10.4049/jimmunol.170.2.711. PMID 12517932. 
  • Wang S, Bajorath J, Flies DB, Dong H, Honjo T, Chen L (May 2003). "Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction". The Journal of Experimental Medicine 197 (9): 1083–91. doi:10.1084/jem.20021752. PMC 2193977. PMID 12719480. 
  • Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, Omura K, Yagita H, Pardoll DM, Chen L, Azuma M (Aug 2003). "Differential binding properties of B7-H1 and B7-DC to programmed death-1". Biochemical and Biophysical Research Communications 307 (3): 672–7. doi:10.1016/S0006-291X(03)01257-9. PMID 12893276. 
  • Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST (Dec 2003). "Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes". Tissue Antigens 62 (6): 492–7. doi:10.1046/j.1399-0039.2003.00136.x. PMID 14617032. 
  • Prokunina L, Gunnarsson I, Sturfelt G, Truedsson L, Seligman VA, Olson JL, Seldin MF, Criswell LA, Alarcón-Riquelme ME (Jan 2004). "The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis". Arthritis and Rheumatism 50 (1): 327–8. doi:10.1002/art.11442. PMID 14730631. 
  • Lin SC, Yen JH, Tsai JJ, Tsai WC, Ou TT, Liu HW, Chen CJ (Mar 2004). "Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus". Arthritis and Rheumatism 50 (3): 770–5. doi:10.1002/art.20040. PMID 15022318. 
  • Prokunina L, Padyukov L, Bennet A, de Faire U, Wiman B, Prince J, Alfredsson L, Klareskog L, Alarcón-Riquelme M (Jun 2004). "Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope". Arthritis and Rheumatism 50 (6): 1770–3. doi:10.1002/art.20280. PMID 15188352. 
  • Sanghera DK, Manzi S, Bontempo F, Nestlerode C, Kamboh MI (Oct 2004). "Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies". Human Genetics 115 (5): 393–8. doi:10.1007/s00439-004-1172-0. PMID 15322919. 
  • Nielsen C, Laustrup H, Voss A, Junker P, Husby S, Lillevang ST (2005). "A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients". Lupus 13 (7): 510–6. doi:10.1191/0961203303lu1052oa. PMID 15352422. 
  • Johansson M, Arlestig L, Möller B, Rantapää-Dahlqvist S (Jun 2005). "Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus". Arthritis and Rheumatism 52 (6): 1665–9. doi:10.1002/art.21058. PMID 15934088. 
  • Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST (Jun 2005). "Alternative splice variants of the human PD-1 gene". Cellular Immunology 235 (2): 109–16. doi:10.1016/j.cellimm.2005.07.007. PMID 16171790. 
  • Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (Nov 2005). "CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms". Molecular and Cellular Biology 25 (21): 9543–53. doi:10.1128/MCB.25.21.9543-9553.2005. PMC 1265804. PMID 16227604. 
  • Kobayashi M, Kawano S, Hatachi S, Kurimoto C, Okazaki T, Iwai Y, Honjo T, Tanaka Y, Minato N, Komori T, Maeda S, Kumagai S (Nov 2005). "Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren's syndrome". The Journal of Rheumatology 32 (11): 2156–63. PMID 16265694. 

External links

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