Plasma Autoantibodies Disease Associations

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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 cirrhosis[1]

Autoantibodies are often detected many years before the onset of disease[2].

Antinuclear antibodies[3]

  • Antinuclear factor (ANF):
  • 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. 

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

Parietal cell antibodies[6]

  • 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

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 mellitus[8, 9]:

  • 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 antibodies[10]

Raised levels of antibodies against thyroid peroxidase, thyroglobulin and TSH receptor are commonly found in autoimmune thyroid disease[11]

  • Thyroglobulin:
  • 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' disease[12].

Antisperm antibodies

Specific and characteristic of immunological infertility.

Steroid cell antibodies

Present in Addison's disease and autoimmune gonadal failure.

  • Myasthenia gravis:
    • Acetylcholine receptor antibody is associated in most patients with myasthenia gravis[13].
  • 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.
  • 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.

Cardiac muscle antibodies are associated with heart failure, myocarditis and dilated cardiomyopathy[16].

  • Intra-epidermal/desmosome antibody (pemphigus antibody) is associated with all forms of pemphigus[17].
  • Basement membrane zone antibody (pemphigoid antibody) is associated mainly with bullous pemphigoid[18].

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Further reading and references

  1. Tan EM; Autoantibodies, autoimmune disease, and the birth of immune diagnostics. J Clin Invest. 2012 Nov 1122(11):3835-6. doi: 10.1172/JCI66510. Epub 2012 Nov 1.

  2. Scofield RH; Autoantibodies as predictors of disease. Lancet. 2004 May 8363(9420):1544-6.

  3. Mahler M, Meroni PL, Bossuyt X, et al; Current concepts and future directions for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. J Immunol Res. 20142014:315179. doi: 10.1155/2014/315179. Epub 2014 Apr 27.

  4. Robertson JM, James JA; Preclinical systemic lupus erythematosus. Rheum Dis Clin North Am. 2014 Nov40(4):621-35. doi: 10.1016/j.rdc.2014.07.004. Epub 2014 Sep 2.

  5. Aletaha D, Bluml S; Therapeutic implications of autoantibodies in rheumatoid arthritis. RMD Open. 2016 May 172(1):e000009. doi: 10.1136/rmdopen-2014-000009. eCollection 2016.

  6. Rusak E, Chobot A, Krzywicka A, et al; Anti-parietal cell antibodies - diagnostic significance. Adv Med Sci. 2016 Jan 1361(2):175-179. doi: 10.1016/j.advms.2015.12.004.

  7. Oertelt S, Rieger R, Selmi C, et al; A sensitive bead assay for antimitochondrial antibodies: Chipping away at AMA-negative primary biliary cirrhosis. Hepatology. 2007 Mar45(3):659-65.

  8. Rekers NV, von Herrath MG, Wesley JD; Immunotherapies and immune biomarkers in Type 1 diabetes: A partnership for success. Clin Immunol. 2015 Nov161(1):37-43. doi: 10.1016/j.clim.2015.05.021. Epub 2015 Jun 27.

  9. LaGasse JM, Brantley MS, Leech NJ, et al; Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study. Diabetes Care. 2002 Mar25(3):505-11.

  10. Sinclair D; Clinical and laboratory aspects of thyroid autoantibodies. Ann Clin Biochem. 2006 May43(Pt 3):173-83.

  11. Khan FA, Al-Jameil N, Khan MF, et al; Thyroid dysfunction: an autoimmune aspect. Int J Clin Exp Med. 2015 May 158(5):6677-81. eCollection 2015.

  12. Sheehan MT; Biochemical Testing of the Thyroid: TSH is the Best and, Oftentimes, Only Test Needed - A Review for Primary Care. Clin Med Res. 2016 Jun14(2):83-92. doi: 10.3121/cmr.2016.1309. Epub 2016 May 26.

  13. Nacu A, Andersen JB, Lisnic V, et al; Complicating autoimmune diseases in myasthenia gravis: a review. Autoimmunity. 201548(6):362-8. doi: 10.3109/08916934.2015.1030614. Epub 2015 Apr 27.

  14. Silvarino R, Noboa O, Cervera R; Anti-glomerular basement membrane antibodies. Isr Med Assoc J. 2014 Nov16(11):727-32.

  15. Schulte-Pelkum J, Radice A, Norman GL, et al; Novel clinical and diagnostic aspects of antineutrophil cytoplasmic antibodies. J Immunol Res. 20142014:185416. doi: 10.1155/2014/185416. Epub 2014 Jun 5.

  16. Kaya Z, Leib C, Katus HA; Autoantibodies in heart failure and cardiac dysfunction. Circ Res. 2012 Jan 6110(1):145-58. doi: 10.1161/CIRCRESAHA.111.243360.

  17. Santoro FA, Stoopler ET, Werth VP; Pemphigus. Dent Clin North Am. 2013 Oct57(4):597-610. doi: 10.1016/j.cden.2013.06.002. Epub 2013 Aug 12.

  18. Leuci S, Gurcan HM, Ahmed AR; Serological studies in bullous pemphigoid: a literature review of antibody titers at presentation and in clinical remission. Acta Derm Venereol. 2010 Mar90(2):115-21. doi: 10.2340/00015555-0819.