Plasma autoantibodies

Autoimmune disease can be either organ-specific illnesses (eg, thyroid disease, type 1 diabetes mellitus, myasthenia gravis) or systemic illnesses (eg, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE)). The cause of autoimmune damage may be mainly due to either autoantibodies or autoimmune T lymphocytes. Nearly all autoimmune diseases are associated with circulating autoantibodies, which may also be found associated with non-related illnesses and in healthy individuals.

The immune system is able to identify cellular factors that initiate tumour formation by making autoantibodies to tumour-associated antigens - eg, novel autoantibodies have been detected during the transition period to hepatocellular carcinoma In a patient with liver cirrhosis¹.

Autoantibodies are often detected many years before the onset of disease².

Rheumatology

Antinuclear antibodies³

• Antinuclear factor (ANF):
  

  • Raised ANF is almost always present in SLE⁴.

  • It is also associated with drug-induced lupus erythematosus (LE), systemic sclerosis (scleroderma), Sjögren's syndrome, polymyositis and dermatomyositis, mixed connective tissue disorder and autoimmune hepatitis.

  • Drugs associated with drug-induced LE are isoniazid, phenytoin, hydralazine, methyldopa, chlorpromazine, penicillamine and minocycline.

  • Raised ANF may also be seen in Addison's disease, idiopathic thrombocytopenic purpura (ITP), Hashimoto's thyroiditis, autoimmune haemolytic anaemia and type 1 diabetes mellitus; occasionally a positive ANF is found in normal elderly people.

• Single-stranded DNA antibody: 70% of patients with SLE but also in other autoimmune rheumatic and inflammatory conditions, and is therefore of limited clinical value.

• Anti-double stranded DNA antibody (anti-dsDNA): associated with SLE. It is a less sensitive but more specific test than ANF and is rarely positive in other conditions. It correlates with disease activity.

• Anti-histone antibodies: associated with SLE and drug-induced LE.

• Anti-Sm (Smith): very specific but relatively insensitive for SLE. It is associated with central nervous system involvement and nephritis in SLE.

• Anti-RNP: mixed connective tissue disease. It is specific for SLE but lacks sensitivity. Anti-RNP is also associated in a minority of patients with systemic sclerosis and scleroderma.

• Anti-Ro: primary Sjögren's syndrome, SLE.

• Anti-LA: primary Sjögren's syndrome, SLE.

• Centromere: scleroderma, systemic sclerosis.

• Nucleolar:
  

  • Nucleolar RNA: systemic sclerosis.

  • Scl-70: diffuse cutaneous systemic sclerosis (dcSSc).

  • PM/Scl: polymyositis, systemic sclerosis overlap syndrome.

• Cytoplasmic:
  

  • Jo-1 (an aminoacyl-tRNA synthetase antibody): dermatomyositis.

  • Ribosomal-P: SLE (often in absence of anti-DsDNA antibodies).

Rheumatoid factor

• Rheumatoid factor is a significant serological marker for RA but is a poor marker for monitoring disease.⁵

• High levels are associated with RA and Sjögren's syndrome.

• Other disease associations include chronic hepatitis, chronic viral infection, tuberculosis, leprosy, leukaemia, dermatomyositis, infectious mononucleosis, systemic sclerosis and SLE.

• IgM rheumatoid factor is found in 2-10% of healthy adults.

Antiphospholipid antibodies

• Anticardiolipin antibodies are the most commonly detected antiphospholipid antibodies.

• Anticardiolipin antibodies are associated with primary antiphospholipid syndrome. They are also present in some patients with SLE.

• IgG anticardiolipin antibodies are more significant than IgM anticardiolipin antibodies.

Gastroenterology

Intrinsic factor antibodies
Very specific and virtually diagnostic for pernicious anaemia but sensitivity is only 40-75%.

Parietal cell antibodies⁶

• Associated with autoimmune gastritis but are also found in pernicious anaemia, autoimmune hepatitis and chronic liver disease.

• Parietal cell antibodies may also be found in elderly patients without autoimmune disease.

IgA anti-tissue transglutaminase (anti-tTG), antigliadin and endomysial antibodies (EMAs)

• These are sensitive and specific for coeliac disease.

• IgA EMAs are slowly being replaced by IgA anti-tTG as the method of choice for screening for coeliac disease (high sensitivity and specificity for both coeliac disease and dermatitis herpetiformis).

• tTG is an intracellular enzyme which is the major autoantigen of anti-endomysial antibodies (anti-EMAs). The IgG equivalents of these tests are less specific and sensitive but may be present if the patient has IgA deficiency, which can be associated with coeliac disease.

Antimitochondrial antibodies

• May be present in primary biliary cirrhosis (95% of patients)⁷, autoimmune hepatitis, other causes of cirrhosis, RA, syphilis, SLE and thyroiditis.

• There are several different types of mitochondrial antibodies (MAs):
  

  • M2 antimitochondrial antibodies (AMAs) are found in primary biliary cirrhosis.

  • M1 is associated with syphilis.

  • M2 and M3 are associated with primary biliary cirrhosis.

  • M6 is associated with isoniazid-induced hepatitis.

Anti-smooth muscle antibodies

• High titres are found in 95% of patients with autoimmune active hepatitis.

• May also be found with primary biliary cirrhosis, primary sclerosing cholangitis, infectious mononucleosis, primary pulmonary hypertension and 3% of healthy individuals.

Endocrinology

Antibodies in diabetes mellitus

The presence of two or more of the following is associated with a high incidence of the development of type 1 diabetes mellitus⁸⁹:

• Glutamic acid decarboxylase (GAD) antibody.

• Islet cell antibody: prevalence at diagnosis is 75%, first-degree relatives 2-5% and the general population 0.4%.

• Insulin antibody: present in 40% of newly diagnosed type 1 diabetes mellitus. Titres of both islet cell and insulin antibody diminish once beta cell destruction is advanced and are not usually detected after the first year of disease.

Thyroid antibodies¹⁰

Raised levels of antibodies against thyroid peroxidase, thyroglobulin and TSH receptor are commonly found in autoimmune thyroid disease¹¹.

• Thyroglobulin:
  

  • Hashimoto's thyroiditis, primary hypothyroidism, hyperthyroidism, colloid goitre, thyroid cancer, pernicious anaemia, Addison's disease and diabetes mellitus.

  • Also found in healthy individuals.

• Thyrotropin receptor antibodies:
  

  • Useful in the diagnosis of Graves' disease but do not distinguish between stimulatory or inhibitory antibodies.

• Thyroid peroxidase antibodies:
  

  • The presence of anti-TPO antibodies is a hallmark of autoimmune thyroid disease, especially Hashimoto's thyroiditis, but also being highly prevalent in postpartum thyroiditis and Graves' disease¹².

Antisperm antibodies

Specific and characteristic of immunological infertility.

Steroid cell antibodies

Present in Addison's disease and autoimmune gonadal failure.

Neurology

• Myasthenia gravis:
  

  • Acetylcholine receptor antibody is associated in most patients with myasthenia gravis¹³.

• Antibodies in peripheral neuropathy:
  

  • Ganglioside M1 (GM1): patients with multifocal motor neuropathy and less frequently in Guillain-Barré syndrome (GBS).

  • Antibodies to myelin-associated glycoproteins in multiple sclerosis, myasthenia gravis and SLE.

• Neurological manifestations of malignancy:
  

  • Enteric neuronal antibodies: small cell carcinoma of bronchus.

  • Antineuronal nuclear antibodies (ANNA): small cell carcinoma of lung, carcinoma of breast.

  • Purkinje cell antibodies: gynaecological cancer, Hodgkin's disease.

  • Retinal antibodies: small cell carcinoma of lung.

Renal disease¹⁴

• Anti-glomerular basement membrane (GBM) antibodies are detected in Goodpasture's syndrome.

• They may also co-exist with antineutrophil cytoplasmic antibody (ANCA) in patients with systemic vasculitis and rapidly progressive glomerulonephritis (RPGN).

• Concentration of GBM antibodies can be used to monitor the patient's response to therapy.

Antineutrophil cytoplasmic antibodies¹⁵

• ANCA: associated with necrotising vasculitis and vasculitis associated with rheumatic and inflammatory bowel disease.

• There are two major types of indirect immunofluorescence staining:
  

  • C-ANCA (cytoplasmic): associated with granulomatosis with polyangiitis (GPA), micropolyarterits, Churg-Strauss syndrome, polyarteritis nodosa and RPGN.

  • P-ANCA (perinuclear): associated with microscopic polyangiitis, Churg-Strauss syndrome, anti-GBM disease, crescenteric glomerulonephritis and GPA.

Cardiology

Cardiac muscle antibodies are associated with heart failure, myocarditis and dilated cardiomyopathy¹⁶.

Dermatology

• Intra-epidermal/desmosome antibody (pemphigus antibody) is associated with all forms of pemphigus¹⁷.

• Basement membrane zone antibody (pemphigoid antibody) is associated mainly with bullous pemphigoid¹⁸.