Not to be confused with Heterosubtypic Immunity.

Cross-reactivity applies to the reaction between two different species as opposed to the self-reactivity. In chemistry it means a reaction between two different molecules. At the same time each of these molecules is able to react with the identical molecule, or as it is usually described, to react with itself. In immunology, the cross-reactivity has a more narrow meaning of the reaction between an antibody and an antigen that differs from the immunogen. It is sometimes also referred to as crossimmunity or cross-protective immunity,[1] although cross-reactivity does not necessarily infer cross-protection. A few examples of cross-reactivity have been confirmed in humans, one of which involves influenza virus-specific CD8+ T cell and hepatitis C virus antigens.[2]

An adaptive immune response is specific to the antigen that stimulated it (called the immunogen). However, many naturally occurring apparent antigens are actually a mixture of macromolecules (for example, from pathogens, toxins, proteins, or pollen) comprising several epitopes. Contact with a complex antigen such as a virus will stimulate multiple immune responses to the virus' different macromolecules as well as the individual epitopes of each macromolecule. For example, the tetanus toxin is a single protein macromolecular antigen but will stimulate many immune responses due to the tertiary structure of the protein yielding many different epitopes. The toxin that creates the immune response will have an epitope on it that stimulates the response. Denaturing the protein may 'disarm' its function but allow the immune system to have an immune response thus creating an immunity without harming the patient.

In medical tests, including rapid diagnostic tests, cross-reactivity can be either confounding or helpful, depending on the instance. An example of confounding that yields a false positive error is in a latex fixation test when agglutination occurs with another antigen rather than the antigen of interest. An example of helpful cross-reactivity is in heterophile antibody tests, which detect Epstein-Barr virus using antibodies that grew for other antigens. Cross-reactivity is also a commonly evaluated parameter for the validation of immune and protein binding based assays such as ELISA and RIA. In this case it is normally quantified by comparing the assays response to a range of similar analytes and expressed as a percentage. In practice, calibration curves are produced using fixed concentration ranges for a selection of related compounds and the midpoints (IC50) of the calibration curves are calculated and compared. The figure then provides an estimate of the response of the assay to possible interfering compounds relative to the target analyte.


Example of tissue cross-reactivity on human tissue microarray

Hevein-like protein domains are a possible cause for allergen cross-reactivity between latex and banana.[3]

Cross-reactivity may be caused by identical carbohydrate structures on unrelated proteins from the same or different species. Such cross-reactive carbohydrate determinants (CCDs) are an issue in allergy diagnosis, where about a fifth of all patients displays IgE antibodies against Asn-linked oligosaccharides (N-glycans) containing core α1,3-linked fucose.[4] As CCDs apparently do not elicite allergic symptoms, a positive in vitro test based on IgE binding to CCDs must be rated as false positive.

Applications in drug development: Tissue cross reactivity (TCR) assay is a standard method based on immunohistochemistry, required prior to phase I human study for therapeutic antibodies.


  1. Porrozzi, R; Teva, A; Amaral, VF; Santos Da Costa, MV; Grimaldi Jr, G (2004). "Cross-immunity experiments between different species or strains of Leishmania in rhesus macaques (Macaca mulatta)". The American journal of tropical medicine and hygiene. 71 (3): 297–305. PMID 15381810.
  2. Kasprowicz, Victoria; Ward, Scott M.; Turner, Alison; Grammatikos, Alexandros; Nolan, Brian E.; Lewis-Ximenez, Lia; Sharp, Charles; Woodfruff, Jenny; et al. (2008). "Defining the directionality and quality of influenza virus–specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus". Journal of Clinical Investigation. 118 (3): 1143–53. doi:10.1172/JCI33082. PMC 2214846Freely accessible. PMID 18246203.
  3. Mikkola, JH; Alenius, H; Kalkkinen, N; Turjanmaa, K; Palosuo, T; Reunala, T (1998). "Hevein-like protein domains as a possible cause for allergen cross-reactivity between latex and banana". The Journal of allergy and clinical immunology. 102 (6 Pt 1): 1005–12. doi:10.1016/S0091-6749(98)70339-2. PMID 9847442.
  4. Altmann, F (2007). "The role of protein glycosylation in allergy". Int Arch Allergy Immunol. 142 (2): 99–115. doi:10.1159/000096114. PMID 17033195.

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