Autoimmune diseases: intracellular autoantigen antibodies Vs extracellular autoantigen antibodies

Intracellular autoantigen antibodies Vs extracellular autoantigen antibodies. An important feature of autoimmune diseases: the production of autoantibodies (Autoantibodies) against self proteins (autoantigens).

Autoantibodies in blood or cerebrospinal fluid are also an important basis for the diagnosis of autoimmune diseases. Among the more than 20,000 proteins, it is now found that about 100 of them are used as autoantigens in 70 autoimmune diseases, including intracellular proteins and extracellular proteins.

Intracellular autoantigens are usually not bound by autoantibodies and are autoimmune biomarkers that represent abnormal immune cell activity.

On the contrary, extracellular autoantibodies can easily reach their targets and directly cause diseases by changing the protein function or abundance of extracellular autoantigens and/or by recruiting complement-mediated cell killing.

Intracellular autoantigen

Autoantigens of intracellular targets, including structural proteins, enzymes, RNA binding proteins, and RNA polymerases. Dead cells, ineffective removal of apoptotic cells, protein modification in the process of inflammatory response, molecular simulation and other mechanisms allow proteins in cells to be recognized by B cells and become self-antigens.

Autoantibodies against intracellular proteins are important biomarkers in many rheumatic diseases, including Sjogren’s syndrome, systemic lupus erythematosus, systemic sclerosis and myositis.

Intracellular autoantigen antibodies Vs extracellular autoantigen antibodies

Sjogren’s syndrome is an autoimmune disease dominated by dry mouth and eyes. The main autoantibodies are directed against SSA and SSB. SSA consists of two different self-antigen proteins, Ro52 (TRIM21) and Ro60. SSB contains a single protein La. They are widely expressed, not just confined to the salivary glands. Both Ro60 and La are intracellular RNA binding proteins. Ro52 is an important immunoglobulin receptor in the cell, which mediates ubiquitination-dependent destruction and internalization of the immunoglobulin-pathogen complex. The entire protein complex of Ro52, immunoglobulin and virus may be recognized as “foreign”.

Systemic lupus erythematosus (SLE) is characterized by immune activation and extensive tissue destruction, and a high incidence of autoantibodies against intracellular proteins and DNA. In addition to autoantibodies to Ro52, Ro60 and La proteins, RNA binding proteins including RNP-A (SNRPA1), U1-70K (SNRNP70) and Sm-D3 (SNR-PD3) are also important diagnostic autoantigens. Autoantibodies and autoantigens form immune complexes to activate complement is the main pathogenesis. However, the precise mechanism of why RNA-binding protein becomes a self-antigen is not clear.

Autoantibodies against certain intracellular autoantigens are associated with specific SLE symptoms. For example, the presence of RNP-A autoantibodies is associated with patients with Raynaud’s skin symptoms.

Myositis represents a variety of disease subtypes, including autoimmune-mediated muscle inflammation and subsequent muscle tissue destruction. The known autoantigens of myositis as targets of autoantibodies are intracellular proteins.
According to the autoantibody reaction, the disease can be divided into four subtypes: anti-synthetase syndrome (Jo1, PL7, TARS, ARS and other tRNA synthetases), idiopathic dermatomyositis (Mi2 histone acetylase, MDA-5 (IFIH1) )), inclusion body myositis or immune-mediated necrotizing myopathy (HMGCR).

The autoimmunity of systemic sclerosis (scleroderma) is manifested by vascular dysfunction, inflammation, and changes in the fiber structure of the skin and internal organs. Autoantigens include Ro52, Ro60, various intracellular proteins, topoisomerase 1, plasmid proteins (CENPA and CENPB), PM/SCL (EXOSC9 and EXOSC107) and RNA polymerase 3 complex (POLR3A and POLR3K). The autoantibody diagnosis of systemic sclerosis requires a multi-molecule panel.

Type I diabetes (T1D) is an autoimmune disease that is common in children’s immune destruction of insulin-producing cells mediated by T cells in the pancreas. Autoantibodies against one extracellular protein and several intracellular proteins are usually found in T1D and are important biomarkers of the disease.
Serum insulin (extracellular autoantigen) autoantibodies, but anti-insulin autoantibodies do not cause disease because they do not cause the destruction of insulin-producing cells.

Intracellular autoantigen IA-2 (PTRN) is a receptor type tyrosine protein phosphatase, which is confined to the dense core vesicle membrane and is highly expressed in the brain and pancreas.

Two other intracellular proteins, glutamate decarboxylase/GAD65 (GAD2) and Znt8 (SLC30A8), are also targets of autoantibodies in T1D. GAD65 is an enzyme responsible for the synthesis of the neurotransmitter-aminobutyric acid (GABA). Autoantibodies against GAD65 are not specific for T1D and can be found in several autoimmune diseases of the central nervous system, including stiff person syndrome and autoimmune encephalitis. Znt8 is a zinc transporter that is abundantly expressed on the insulin-secreting granules of pancreatic cells.

Extracellular autoantigen

Autoantibodies against extracellular proteins can directly cause various autoimmune diseases. This direct pathogenicity is caused by autoantibodies binding to extracellular proteins to disrupt the normal function of key proteins or pathways, and/or by triggering antibody-dependent complement killing.

The pathogenicity of autoantibodies needs to meet several criteria:

1) Specific autoantibodies are strongly related to the relevant clinical manifestations of the disease and are absent in healthy individuals or other diseases,

2) Autoantigens are specifically localized in diseased tissues,

3) The level of autoantibodies is correlated with disease activity.

Validation of the pathogenicity of autoantibodies usually involves animal models in which passive transfer of autoantibodies or antigen-induced immunity in patients can induce clinical features of the disease.

Intracellular autoantigen antibodies Vs extracellular autoantigen antibodies

Myasthenia gravis (Myasthenia gravis) is a muscle autoimmune disease with pathogenic autoantibodies that interfere with cholinergic receptors and other proteins at neuromuscular junctions. The main autoantibody target of about 85% of patients with myasthenia gravis is the extracellular n-terminal region of the a1 subunit of the nicotinic acetylcholine receptor/nAChR (CHRNA1), which is highly abundant in skeletal muscle. Autoantibodies to muscle-related cell surface tyrosine kinase (MUSK) and low-density lipoprotein receptor-related protein (LRP4) are less common and are found in approximately 1-10% and 1-3% of cases, respectively.

Autoimmune diseases of the central nervous system involve autoantibodies to extracellular proteins found in neurons or glial cells. For example, autoantibodies against the aquaporin-4 (AQP4) channel cause optic neuritis (NMO/Devic’s disease).

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) can also cause autoimmune demyelinating diseases in NMO. Autoantibodies against NMDAR (such as GRIN1) subunits on the surface of neurons can cause encephalitis and other neurological problems.

Several autoimmune diseases of the kidney are driven by autoantibodies to extracellular proteins. Anti-Glomerular Basement Membrane Disease (Goodpasture’s), known as anti-GBM disease, is caused by IV collagen (COL4A3) and is abundantly expressed in the lungs and kidneys. Anti-collagen autoantibodies cause complement activation and leukocyte infiltration, damage the basement membrane in the glomerular capillaries.

Another autoimmune disease, membranous nephropathy, shows focal autoantibodies in the glomerular basement membrane and renal epithelial layer adjacent to the podocyte foot process (for: phospholipase A2 receptor/PLA2R and thrombus type 1 domain 7A /THSD7A) deposition.

Autoantibodies to extracellular target proteins are generally thought to cause the corresponding loss of function. However, in Graves’ thyroiditis, the autoantibodies found on the follicular thyroid cells bind to the thyroid hormone stimulating receptor (THSR), which has an agonist-like activity, overactivating downstream signals and leading to high levels of circulating thyroid hormone. Clinical symptoms include hyperthyroidism, eye disease, and crystal skin disease.

Autoantibodies against circulating hormones, growth factors and cytokines can cause a variety of autoimmune-mediated diseases. Cytokines are especially important because they play a key role in the maturation of immune cells and coordinate their response to pathogens. Some acquired autoimmune immunodeficiencies are caused by anti-cytokine autoantibodies, such as alveolar protein disease caused by GM-CSF autoantibodies. Autoantibodies block signal transduction, thereby preventing the downstream pathway and maturation of macrophages in the lungs. , Resulting in excessive accumulation of surfactants and other lipoproteins in the lower respiratory tract.
With anti-IFN-γ autoantibodies, patients with severe mycobacterial infection.