IgG4-associated diseasesZ86.2

The term "IgG4-related diseases" was used to describe a group of inflammatory, often eosinophilic and fibrosing autoimmune diseases that were first described in 2003 in a patient with autoimmunological pancreatitis. To describe the organ-spanning nature of this systemic disease, the term " IgG4-related autoimmune diseases" was introduced. It soon became apparent that this is a family of diseases that can affect different organs mono- and/or polytopically.

IgG4-associated autoimmune diseases, which can be grouped under a common etiopathogenetic concept, include various organ diseases. Some of them have been newly defined, others have been known for a long time as entities under specific names:

• Retroperitoneum: Retroperitoneal fibrosis (Ormond's disease)(N13.5)
• Salivary glands: IgG4-associated chronic sclerosing sialadenitis - so-called Küttner tumor (adenitis of the submandibular gland is rare and affects about 2% of all pat. with IgG4-associated autoimmune diseases. Clinically striking is an indolent, dermal, displaceable mass usually located unilaterally on the undersurface of the mandible).
• Salivary and lacrimal glands: IgG4-associated adenitis, so-called Mikulicz syndrome (K11.8)
• IgG4-associated chronic sclerosing sialadenitis (K11.8) so-called Küttner tumor
• Lung: inflammatory pseudotumor of the lung
• Pancreas: IgG4-associated autoimmune pancreatitis (K86.1) - AIP- (the diagnosis is usually made incidentally by revealing a tumor-like mass in the pancreatic head. IgG4 in serum usually elevated. Not infrequently positive ANA and AK against carbonic anhydrase II. The changes respond well to steroids).
• Liver: IgG4-associated cholangitis ( Pat. > 60 years old; m>w=8:1. In the versch. A disproportionate number of patients with high exposure to solvents, industrial dusts/oils, and pesticides were found in the different collectives. Diagnosis is made by imaging, elevated serum IgG4 level; in about 50-80% of cases there is concordant IgG4-associated autoimmune pancreatitis).
• Kidney: IgG4-associated nephropathy/ IgG4-associated tubulointerstitial nephropathy (tubulointerstitial nephritis is most commonly observed. This is associated with either acute renal failure or chronic insidious renal failure. Imaging shows renal masses, proteinuria, hematuria, and decreased complement. The histologic substrate shows IgG4-positive plasma cells and marked interstitial fibrosis; furthermore, deposits of immune complexes along the tubular basement membrane.
• Lymph nodes: IgG4-associated lymphadenopathy

• Thyroid: Riedel's stroma (Eo6.5). Rare Riedel's struma is classified as sclerosing thyroiditis among IgG4-associated autoimmune diseases. The "iron-hard" goiter can lead to narrowing of the trachea and recurrent paresis. Malignancy exclusion! A fibrosing subtype of Hashimoto's thyroiditis is also classified in this group.

• Skin: Granuloma (eosinophilicum) faciale (L92.2) / Erythema elevatum diutinum (L95.1)

• Nasopharynx: Eosinophilic angiocentric fibrosis.

The (common) pathogenesis of this family of diseases remains largely unexplained. In particular, the exact pathogenetic function of immunoglobulin G4 in this context is not yet understood. Both autoimmunological and allergic mechanisms are being discussed.

The detection of an increased number of regulatory T cells (Treg) in the inflammatory infiltrates suggests a T cell dysregulation with a Th2 accentuation and a Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13, IL-17). The Th2 cytokines activate B cells and regulatory T cells and lead to tissue infiltration of eosinophil granulocytes with increased IgE production. Molecular mimicry is also discussed, whereby a cross-reactivity of bacterial peptide sequences (e.g. Helicobacter pylori ubiquitin ligase with endogenous proteins) is assumed.

Regulatory T cells produce IL-10 and TGF , which leads to plasma cell activation with consecutive production of IgG4. TGF in turn stimulates fibroblasts with fibrosis (diffuse, storiform and/or perivascular - onion-skin-like - see also granuloma faciale), which can be detected in all late-stage diseases. The proliferates lead to inflammatory pseudotumorous tissue proliferation in various organs, which can be detected using different imaging techniques. The further course of the disease is characterized by fibrotic organ dysfunction.

IgG4 and skin: The associated clinical pictures of the skin are characterized by site-specific features. As they frequently occur on exposed areas of skin and are well described clinically and diagnostically (e.g. granuloma (eosinophilicum) faciale), they are also recognized at an early stage. The skin lesions occupy a special position pathogenetically as well as diagnostically and therapeutically. In fact, they allow direct histopathological access at every stage of the disease, so that cross-sectional analyses over time are also possible. The not uncommon concordant occurrence of granuloma faciale with sinonasal eosinophilic angiocentric fibrosis (note: coincidence of 2 rare diseases that can also occur concordantly) suggests a common etiopathogenesis per se, which supports the common pathogenetic concept of IgG4-associated diseases.

The following symptoms could be defined as common features of the family of IgG4-associated autoimmune diseases:

• circumscribed inflammatory tissue proliferations (papules, plaques, nodules, pseudotumorous swellings)
• indicative histological substrate: IgG4-positive lymphoplasmacytic cellular infiltrates, increased tissue concentrations of IgE and IgG4, irregularly expressed histoeosinophilia, (depending on the duration of the disease) stratified and often onion-shell-like configured or swirled (storiform) fibroses
• elevated serum concentrations of IgG4 (>70% of cases)

IgG4 only detectable elevated in about 55% of patients. Correlation with multiple organ involvement/severe course, peripherally circulating plasmablasts as activity markers, eosinophilia, IgE elevated.

The consistent histopathologic correlate is a lymphoplasmacytic infiltrate with IgG4-positive plasma cells, which leads to the histologic characteristics of storiform fibrosis and obliterative phlebitis. Eosinophilic granulocytes are frequently found in varying densities (this cellular component used to give granuloma faciale its name: granuloma eosinophilicum faciale).

The number of IgG4-positive plasma cells is determined by counting the cells per visual field or by calculating the quotient of IgG4- and IgG-bearing plasma cells. At > 40 % IgG4-positive plasma cells, the diagnosis of IgG4-associated (auto)immune disease can be considered certain.

Probably the first description of an IgG4-associated disease in the salivary gland was made by Mikulicz-Radecki. Later work identified the mononuclear infiltrate in the so-called Mikulicz syndrome (K11.8) as IgG4-positive plasma cells.

The role of IgG4 in the pathogenesis of immediate-type allergic reactions is not yet fully understood.

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