IgG4-associated diseases Z86.2

A group of inflammatory, often eosinophilic and fibrosing autoimmune diseases was summarizedunder the term "IgG4-associated diseases", which was described for the first time in 2003 in a patient with autoimmunological pancreatitis. They are characterized by the presence of antigen-specific autoantibodies of the IgG4 subclass and include well-characterized diseases such as muscle-specific kinase myasthenia gravis, pemphigus and thrombotic thrombocytopenic purpura.

The IgG4 subclass is considered immunologically "inert and functionally monovalent" due to structural differences to other IgG subclasses. IgG4 usually develops after chronic exposure to an antigen and competes with other antibody types, thereby "blocking" their pathogenic effector mechanisms. Accordingly, in the context of IgG4 autoimmunity, the pathogenicity of IgG4 is associated with the blocking of enzymatic activity or a particular protein-protein interaction of the target antigen.

To describe the cross-organ character of this systemic disease, the term " IgG4-related autoimmune diseases" was introduced, a family of diseases that can affect different organs mono- and/or polytopically.

The IgG4-associated autoimmune diseases include various organ diseases. Organ diseases can be listed, some of which have been newly defined and some of which have long been known as entities under specialized names. A modified classification system based on Witebsky 's postulates (for the determination of IgG4 pathogenicity in IgG4 autoimmune diseases) results in 3 classes of IgG4 autoimmune diseases (Koneczny I 2018):

• Class I, in which IgG4 pathogenicity is confirmed by using subclass-specific autoantibodies in animal models and/or in vitro models of pathogenicity;
• Class II, in which IgG4 pathogenicity is strongly suspected but lacks validation through the use of subclass-specific antibodies in in vitro pathogenicity models or animal models; and
• Class III with insufficient data or a pathogenicity mechanism associated with multivalent antigen binding.

In detail, the following diseases are classified as IgG4-associated:

• 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 patients with IgG4-associated autoimmune diseases. Clinically conspicuous is a mostly unilateral, indolent, rough, displaceable mass located on the underside of the lower jaw).
• 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 accidentally by the discovery of a tumor-shaped mass in the head of the pancreas. IgG4 in serum usually elevated. Often positive ANA and AK against carbonic anhydrase II. The changes respond well to steroids).
• Liver: IgG4-associated cholangitis (patients > 60 years old; m>w=8:1. A disproportionately high proportion of patients with high exposure to solvents, industrial dust/oils and pesticides were found in the various 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 frequently observed. This is accompanied either by acute renal failure or chronic insidious renal insufficiency. Renal masses are found on imaging; furthermore proteinuria, hematuriaand hypocomplementemia.
• Lymph nodes: IgG4-associated lymphadenopathy.

• Thyroid gland: Riedel's goiter (Eo6.5). The rare Riedel's goiter is classified as a sclerosing thyroiditis among the IgG4-associated autoimmune diseases. The "iron-hard" goiter can lead to narrowing of the trachea and recurrent paresis. Malignoma 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); Pemphigus vulgaris (L10.0), Pemphigus foliaceus (L10.2).

• 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 increase in IgG4-associated nephropathies after COVID-19 vaccination is noteworthy (Nakamura F et al. 2023).

T-cell dysregulation: The detection of an increased number of regulatory T cells (Treg) in the inflammatory infiltrates suggests T-cell dysregulation with 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: Molecular mimicry is being discussed, whereby a cross-reactivity of bacterial (or viral) peptide sequences (e.g. Helicobacter pylori ubiquitin ligase with endogenous proteins) is assumed. An analogous reaction is suspected in endemic pemphigus foliacus, where molecular mimicry with desmogleins that enter the body via mosquito bites takes place.

Treg: Regulatory T cells (Treg) 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 mRNA vaccination: It has been proven that frequent mRNA vaccinations lead to IgG class conversion to IgG4. Apparently IL-4/IL-10 are involved. IgG4-associated autoimmune pancreatitis, IgG4-associated lung diseases and recurrences of IgG4-associated nephritis have been observed after mRNA vaccinations. Furthermore, in contrast to IgG1 and IgG3, IgG4 has a low effector function and only low antiviral activity (Nakamura F et al. 2023).

IgG4 and skin: The associated clinical pictures of the skin are localized. 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 can be defined as common features of the family of IgG4-associated autoimmune diseases:

• circumscribed inflammatory tissue proliferation (papules, plaques, nodules, pseudotumorous swellings)
• indicative histological substrate: fine tissue definable IgG4-positive lymphoplasmacellular infiltrates, increased tissue concentration of IgE and IgG4, irregularly pronounced, possibly formative histoeosinophilia, (depending on the duration) layered, often onion-skin-like or swirled (storiform) fibroses
• Increased serum concentrations of IgG4 (>70% of cases)

IgG4 is only found to be elevated in around half of patients.

IgG4 elevations correlate with multiple organ involvement/severe course, peripheral circulating plasmablasts as activity markers, eosinophilia and elevated IgE.

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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