Immune mechanisms in polymyositis and dermatomyositis

Clinically: weakness and low endurance of skeletal muscle

Histopathologically: the presence of T cells, macrophages, dendritic cells, B cells and plasma cells in the muscle tissue

80% of patients-Autoantibodies are common and are present

Immune mechanisms

genetic risk factor in Caucasian patients: MHC class II genes (HLA-DR3)

(the major role of the HLA-DR is to present antigens to CD4+ T cells)

muscle biopsies of patients with myositis describing both CD4+ and CD8+ T cells and B cells in the inflammatory cell infiltrates

Two distinct patterns of inflammatory cellular infiltrates:

1.      one with the inflammatory cell infiltrates primarily localized to the endomysium surrounding non-necrotic muscle fibres—endomysial infiltrates

2.      another primarily localized to the perimysium surrounding blood vessels—perivascular infiltrates

(these patterns are not mutually exclusive and may sometimes occur together)

Myositisspecific autoantibodies (MSAs):

a majority of patients with PM and DM has at least one MSA if sensitive techniques to identify autoantibodies are utilized

Other autoantibodies can also be found, so-called myositis-associated autoantibodies (MAAs)

(SLE and SS.)

Anti-synthetase autoantibodies

anti-tRNA synthetase autoantibodies: anti-synthetase syndrome

The anti-histidyl antibodies (anti-Jo-1) are the most frequent antisynthetase antibodies

The targets of the tRNA synthetase autoantibodies are ubiquitous enzymes expressed within the cytoplasm, where they attach amino acids to their cognate tRNA. It is unclear how these ubiquitous enzymes become autoantigens and why particularly lungs and muscles become targets of the immune response in these myositis subsets.

1.      proteolytically cleavable form of histidyltRNA synthetase is enriched in the lung and localized to the alveolar epithelium

2.      Newly generated fragments led to maturation of dendritic cells into professional antigenpresenting cells and stimulation of CD4+ T cells, thereby initiating downstream immune cascades

3.      cleaved fragments of antisynthetases could serve as chemokines and cytokines (such as granzyme Bgenerated fragments of Jo-1)

4.      muscle fibres undergoing regeneration have a greater expression of the enzyme than differentiated fibres, making damaged muscle tissue prone to immune reactions targeting histidyl-tRNA synthetase

5.      anti-histidyl-tRNA synthetase antibodies can trigger both innate and adaptive immune responses through activating the type I IFN

B cell

In muscle tissue, molecular characterization of the immunoglobulin variable region sequences showed significant somatic mutation and isotype switching and the presence of clonal expansion and intraclonal variation suggest a local in situ differentiation of B cells\

Patients with anti- Jo-1 autoantibodies, as well as patients with DM, have high serum levels of B cell activating factor (BAFF) compared with other subgroups of myositis patients

T cells

1.      CD4+:
Expansions of T cells were found in broncheoalveolar lavage fluid and CD4+ T cells with the corresponding TCR were detected in infiltrates of muscle tissue. Notably the largest expansions were seen in TCR Vb3 in two patients with anti-Jo-1 autoantibodies being HLA-DR3 positive

2.      CD8+:
Differentiated muscle fibres do not express MHC class I in healthy individuals, but MHC class I molecules are frequently observed in fibres in patients with myositis

3.      CD28null:
PM and DM revealed that a large proportion of the T cells are of the CD28null phenotype CD28null T cells arise due to repeated antigen stimulation and are terminally differentiated and apoptosis resistant. CD4+CD28null T cells and CD8+CD28null T cells are easily stimulated to produce cytokines and they have NK/cytotoxic properties (they contain perforin and granzyme)

T cell shifting the immune balance from suppressive to proinflammatory:

1.      IL-17 mRNA was expressed
(IL-17 in combination with IL-1b led to increased IL-6, HLA class I, CCL20 and nuclear factor (NF)-kB production in myoblasts) Th17 cells may contribute to muscle damage and chronic inflammation

2.      An alternative hypothesis is that Tregs are functionally deficient or that the inflammatory milieu in muscles does not allow Treg suppression

Cytokines

1.      Type I IFNs are of specific interest in PM and DM (Type I IFNs strong inducers of MHC class I and class II molecules) histidyltRNA synthetase can act as an endogenous type I IFN stimulating factor

2.      IL-1a and IL-1b expression is one of the most consistent cytokine patterns in the muscle tissue of patients with PM and DM

3.      The role of TNF in the pathogenesis in IIM is unclear:
TNF blockade has had varying effects and treatment with infliximab may even worsen the inflammation in treatmentresistant cases
TNF may have different roles in different subsets and phases of myositis disease

4.      IL-6, where two case reports have demonstrated a beneficial effect

5.      IL-18 is another molecule that has been demonstrated in muscle tissue and could be interesting to target by IL-18 blockade

6.      IL-15 in a subset of patients with a chronic course

7.      High mobility group box 1 (HMGB1) is an alarmin that can act with proinflammatory properties when released from macrophages or from cells undergoing necrosis

a.      HMGB1 is present with extranuclear and extracellular localization in muscle tissue from patients with PM/DM

b.      HMGB1 can up-regulate MHC class I in muscle fibres and can impair Ca2+ release from the sarcoplasmic reticulum and thus cause impaired muscle contractility and weakness

8.      prostaglandin and leukotriene pathways:
up-regulated in the muscle tissue of myositis patients

9.      immune mechanisms leukotriene B4 (LTB4):

a.      act as a link between the innate and adaptive immune responses

b.      It is a chemoattractant for activated T cells, inducing their migration into inflamed tissue, and is involved in the differentiation of naive murine T cells by inhibiting the differentiation of Tregs and promoting Th17 cells and can also augment cytokine production by activated T cells

Reference:
J Autoimmun. 2014 Feb-Mar; 48-49: 122-7. The clinical features, diagnosis and classification of dermatomyositis. Iaccarino L, Ghirardello A, Bettio S, Zen M, Gatto M, Punzi L, Doria A.