IgG1 protects against renal disease in a mouse model of cryoglobulinaemia

Strait, Richard T.; Posgai, Monica T.; Mahler, Ashley M.; Barasa, Nathaniel; Jacob, Chaim O.; Köhl, Jörg; Ehlers, Marc; Stringer, Keith; Shanmukhappa, Shiva Kumar; Witte, David P.; Hossain, Monir; Khodoun, Marat; Herr, Andrew B.; Finkelman, Fred D.

doi:10.1038/nature13868

Cited by 59 publications

(67 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, additional cerulein hyperstimulation in this context induced far more severe pancreatitis. We also found that chronic pancreatitis in our model showed prominent expression of IgG1, the mouse homologue of human IgG4 19,20,30. In addition, we found that mice with both gliadin and cerulein exposures showed a strong IgG1 staining not only in the plasma cells but also in the stromal, acinar and ductal cells.…”

Section: Discussionsupporting

confidence: 73%

See 1 more Smart Citation

Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

Moon

Kim

et al. 2016

Gut and Liver

View full text Add to dashboard Cite

Background/AimsThe aim of this study was to establish a pathogenetic mechanism of pancreatitis in celiac disease and IgG4-related disease using gluten-sensitive human leukocyte antigen (HLA)-DQ8 transgenic mice.MethodsTransgenic mice expressing HLA-DQ8 genes were utilized. Control mice were not sensitized but were fed gliadin-free rice cereal. Experimental groups consisted of gliadin-sensitized and gliadin-challenged mice; nonsensitized mice with cerulein hyperstimulation; and gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation.ResultsGliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation showed significant inflammatory cell infiltrates, fibrosis and acinar atrophy compared with the control mice and the other experimental groups. The immunohistochemical analysis showed greater IgG1-positive plasma cells in the inflammatory infiltrates of gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation compared with the control mice and the other experimental groups. Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation or gliadin-sensitized and gliadin-challenged mice showed IgG1-stained inflammatory cell infiltrates in the extrapancreatic organs, including the bile ducts, salivary glands, kidneys, and lungs.ConclusionsGliadin-sensitization and cerulein hyperstimulation of gluten-sensitive HLA-DQ8 transgenic mice resulted in pancreatitis and extrapancreatic inflammation. This animal model suggests that chronic gliadin ingestion in a susceptible individual with the HLA-DQ8 molecule may be associated with pancreatitis and extrapancreatic inflammation.

show abstract

Section: Discussionsupporting

confidence: 73%

“…Mouse IgG1 is a homologue of human IgG4 19,20. Blood samples were obtained from the ophthalmic plexus of each group of mice.…”

Section: Methodsmentioning

confidence: 99%

Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

Moon

Kim

et al. 2016

Gut and Liver

View full text Add to dashboard Cite

show abstract

“…In the quartet model, the function of murine IgG1 is to limit IgG‐driven inflammatory processes through engagement with FcγRIIb. It therefore has functions that are similar to those of human IgG4, as recently highlighted by others 60 . Class switching to murine IgG1 and to human IgG4 is promoted by interleukin‐4, and further downstream switching leads from mouse IgG1 and human IgG4 to IgE 61 , 62 .…”

Section: The Quartet Model Of Murine Igg Functionmentioning

confidence: 82%

“…Murine IgG3 antibodies can cause renal disease by precipitating in the glomerular capillaries, as a result of their tendency to self‐aggregate 66 . IgG1 antibodies offer protection against such IgG3‐mediated immune complex immunopathology 60 . Strait and colleagues hypothesize that this may be a result of the inflexibility of IgG1 antibodies, leading to monovalent rather than bivalent binding.…”

Section: The Quartet Model Of Murine Igg Functionmentioning

confidence: 99%

IgG subclass co‐expression brings harmony to the quartet model of murine IgG function

2016

View full text Add to dashboard Cite

A model of murine IgG function is presented in which the co-expression of the IgG subclasses is a central feature, class switching occurs before the commencement of somatic hypermutation, and there is little switching between subclasses. It is named the quartet model to emphasize the harmony that comes from the simultaneous presence of the four subclasses. In this model, IgG3 and IgG2b antibodies are particularly important early in the response, when T-cell help may be limiting. IgG3 initiates inflammation through complement fixation, whereas IgG2b provides early FcγR-mediated effector functions. As T-cell help strengthens, IgG2a antibodies increase the power of the response, whereas IgG1 production helps limit the inflammatory drive and limits immunopathology. The model highlights the fact that murine IgG subclasses function quite differently to human IgG subclasses. This allows them to serve the special immunological needs of a species that is vulnerable because of its small size.

show abstract

“…In contrast, isotypes such as mouse IgG1 that have limited ability to activate effector mechanisms may confer a selective advantage by limiting inflammation and tissue damage in inflammatory and autoimmune disorders. Although we have not tested the ability of IgG1 antibody to limit or reverse the development of EAMG, these considerations raise the possibility that Abs of this isotype (or the analogous human isotype, IgG4) may be useful as a therapeutic in patients with a chronic, Ab-mediated disorder such as MG (Strait et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice

Huda

Strait

Tüzün

et al. 2015

Journal of Neuroimmunology

Self Cite

View full text Add to dashboard Cite

Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to neuromuscular junction (NMJ) damage by anti-acetylcholine receptor (AChR) auto-antibodies and complement. In experimental autoimmune myasthenia gravis (EAMG), which is induced by immunization with Torpedo AChR in CFA, anti-AChR IgG2b and IgG1 are the predominant isotypes in the circulation. Complement activation by isotypes such as IgG2b plays a crucial role in EAMG pathogenesis; this suggested the possibility that IgG1, which does not activate complement through the classical pathway, may suppress EAMG. In this study, we show that AChR-immunized BALB/c mice genetically deficient for IgG1 produce higher levels of complement-activating isotypes of anti-AChR, especially IgG3 and IgG2a, and develop increased IgG3/IgG2a deposits at the NMJ, as compared to wild type (WT) BALB/c mice. Consistent with this, AChR-immunized IgG1−/− BALB/c mice lose muscle strength and muscle AChR to a greater extent than AChR-immunized WT mice. These observations demonstrate that IgG1 deficiency leads to increased severity of EAMG associated with an increase in complement activating IgG isotypes. Further studies are needed to dissect the specific role or mechanism of IgG1 in limiting EAMG and that of EAMG exacerbating role of complement activating IgG3 and IgG2a in IgG1 deficiency.

show abstract

IgG1 protects against renal disease in a mouse model of cryoglobulinaemia

Cited by 59 publications

References 25 publications

Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

IgG subclass co‐expression brings harmony to the quartet model of murine IgG function

IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice

Contact Info

Product

Resources

About