igg4-related disease

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  • IgG4 Related Disease

    Suda Sibunruang, M.D.

  • Outline

    Introduction

    Historical context

    Pathogenesis

    Epidemiology

    Clinical manifestations and laboratory findings

    Treatment and prognosis

  • Outline

    Introduction

    Historical context

    Pathogenesis

    Epidemiology

    Clinical manifestations and laboratory findings

    Treatment and prognosis

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    Immunoglobulin G4 (IgG4)-related disease (IgG4-RD)

    Immune - mediated fibroinflammatory condition

    Can affect almost any organ

    Now being recognized with increasing frequency

  • www.rheumatologynetwork.com ,access May 25, 2015

    IgG4-RD is characterized by Often but not always - elevate serum levels of IgG4

    Cause progressive fibrosis and organ damage

  • Picture from www.mbl.co.jp , access May 25, 2015

    Unifies many diverse conditions, previously thought to be unrelated to each other, as a part of IgG4- RD spectrum

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    Early intervention using glucocorticoids can improve IgG4-related organ dysfunction However, patients often relapse when doses of these agents are tapered Disease has also been associated with an increased incidence of certain malignancies

  • Outline

    Introduction

    Historical context

    Pathogenesis

    Epidemiology

    Clinical manifestations and laboratory findings

    Treatment and prognosis

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

  • Himi T. et. al. Auris Nasus Larynx 2012;39: 917

    Mikulicz-Radecki (1850 - 1905) Illustration of the first reported case of Mikuliczs disease (MD). 42-year-old male developed bilateral, painless swelling of lacrimal, parotid, and submandibular glands.

  • Himi T. et. al. Auris Nasus Larynx 2012;39: 917

  • Himi T. et. al. Auris Nasus Larynx 2012;39: 917

    Immunohistochemistry for IgG4 in salivary glands

    Abundant IgG4-postive cells infiltrate around acinar and ductal cells

    No infiltrating IgG4-positive cells

    Mikuliczs disease Sjogrens syndrome

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

  • Hamano H. et. al. N Engl J Med 2001;344:732-8

    Background Most patients with chronic pancreatitis have a long history of alcohol abuse. Alcohol-induced chronic pancreatitis is characterized by recurrent attacks of abdominal pain, irregular dilatation of pancreatic duct with stone formation, atrophy of pancreatic parenchyma, and pancreatic exocrine and endocrine insufficiency. A unique form of chronic pancreatitis characterized by infrequent attacks of abdominal pain, irregular narrowing of main pancreatic duct, lymphoplasmacytic inflammation of pancreas, and hypergammaglobulinemia and that responds to glucocorticoid. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of pancreas or biliary tract. Methods Measured serum IgG4 concentrations using single radial immunodiffusion & ELISA in 20 patients with sclerosing pancreatitis, 20 normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjogrens syndrome.

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

    CT shows diffuse swelling of pancreas with late phase enhancement and low-density rim

    Endoscopic pancreatography shows diffusely irregular narrowing of main pancreatic duct

    Endoscopic chorangiography shows beaded like and long stenotic biliary duct similar to primary sclerosing cholangitis

  • Hamano H. et. al. N Engl J Med 2001;344:732-8

  • Hamano H. et. al. N Engl J Med 2001;344:732-8

  • Hamano H. et. al. N Engl J Med 2001;344:732-8

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

    Thus a relationship between AIP and IgG4 became apparent

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

    IgG4-related pancreatitis is defined as type 1 AIP

    (lymphoplasmacytic sclerosing Pancreatitis)

    (idiopathic ductcentric pancreatitis )

    (granulocytic epithelial Lesions)

  • Okazaki K. et. al. Autoimmunity Reviews 2014;4518

  • Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:31547

  • Umehara H. et. al. Mod Rheumatol 2012;22:2130

    Comprehensive diagnostic criteria for IgG4-related disease, 2011

  • Umehara H. et. al. International Immunology 2014;26:58595

  • Outline

    Introduction

    Historical context

    Pathogenesis

    Epidemiology

    Clinical manifestations and laboratory findings

    Treatment and prognosis

  • IgG4 antibodies are unusual in many respects

    Torre DE. et. al. Clin Exp Immunol 2015 [Epub ahead of print]

  • Stone JH. et. al. N Engl J Med 2012;366:539-51

  • IgG4 antibodies are unusual in many respects

    Torre DE. et. al. Clin Exp Immunol 2015 [Epub ahead of print]

    A single amino acid difference in hinge region (a serine in lieu of proline found in IgG1) causes inefficient formation of disulfide bridges between heavy chains of molecule

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    Fc-dependent interactions

    Prevent immune-complex-mediated and Fc-receptor-mediated immune responses

    Fc of IgG4 can also interact with various Fc receptors and complement proteins, but has minimal capacity to activate them to induce signalling; thus, these antibodies might antagonize proinflammatory responses mediated by other antibody classes via competitive interaction

  • Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:31547

    Properties of IgG4 antibodies Is often considered to function as an anti-inflammatory antibody Failure to bind efficiently to low-affinity FcRs and C1q renders them inefficient in - Phagocyte activation - Antibody-dependent cellular cytotoxicity - Complement-mediated damage IgG4 antibodies can bind to FcRI, the high-affinity receptor for IgG Fc, but less

    efficiently than IgG1 and IgG3

  • Pathogenesis

    Remains unclear

    Whether IgG4 antibodies are pathogenic in IgG4-RD or are produced in excess in response to inflammatory stimuli due to their anti-inflammatory properties, remains unclear

    Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

  • Stone JH. et. al. N Engl J Med 2012;366:539-51

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    PAMPs and DAMPs are recognized by TLRs and NOD2 in monocytes and basophils initiating signalling that leads to production of BAFF, which promotes Ig class-switching and results in production of IgG4

    BAFF, B-cell-activating factor (also known as, TNF ligand superfamily member 13B, or B-lymphocyte stimulator [BLyS])

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    PAMPs and DAMPs are recognized by TLRs and NOD2 in monocytes and basophils initiating signalling that leads to production of BAFF, which promotes Ig class-switching and results in production of IgG4

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    Activated basophils produce IL-13, and support TH2-cell-dominant inflammation. TH2 cells secrete IL-4 and IL-5, which promote TH2 cell self-propagation via differentiation of naive T cells and activation of eosinophils, respectively.

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    Excess immunoreaction of TH2 cells leads to recruitment of TREG cells, which secrete high levels of IL-10,inducing further class-switching to IgG4, and TGF-, driving severe fibrosis

  • Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:14859

    IL-6 and IL-21 promotes differentiation of naive T cells to TFH cells, leading to formation of ectopic germinal centres, plasmacyte development and active antibody production.

  • Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:31547

    Potential triggers

    Signals from innate immune system may determine state of T helper cell polarization

    When inflammation turns chronic, Treg cells may also be induced to dampen it

    Activated T helper cells and Treg cells may produce an inflammatory cytokine

    Class-switching of autoreactive B cells to IgG4 and IgE and induce the differentiation and expansion of IgG4+ plasma cells

  • Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:31547

    IL-5, IL-13, and TGF- could lead to recruitment of eosinophils and activation of fibroblasts

    Cytokine milieu may also generate profibrotic, alternatively activated macrophages that produce additional fibrogenic cytokines

    Some IgG4 and some IgE antibodies, may be cross-reactive to self-antigen

    B cells that recognize self-antigen are capable of efficient antigen presentation of cognate self-antigens to autoreactive T cells, thereby setting up a vicious cycle

  • Pathogenic model for IgG4-Related Disease

    Torre DE. et. al. Clin Exp Immunol 2015 [Epub ahead of print]

    (1). Dendritic and naive/memory B cells might present antigens to CD4+T lymphocytes triggering their activation (2). Local signals from innate immune system might determine T helper cell polarization and differentiation into effector or memory T cells Activated naive B cells migrate to germinal centre

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