Cross-reactivity

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Cross-reactivity, in a general sense, is the reactivity of an observed agent which initiates reactions outside the main reaction expected. This has implications for any kind of test or assay, including diagnostic tests in medicine, and can be a cause of false positives. In immunology, the definition of cross-reactivity refers specifically to the reaction of the immune system to antigens. There can be cross-reactivity between the immune system and the antigens of two different pathogens, or between one pathogen and proteins on non-pathogens, which in some cases can be the cause of allergies.

Contents

In medical testing

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 with specificity 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 assay's 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.

Applications in drug development

Tissue cross-reactivity assay is a standard method based on immunohistochemistry, required prior to phase I human studies for therapeutic antibodies.

In drug screening, because many urine drug screens use immunoassays there is a certain amount of cross-reactivity. Certain drugs or other chemicals can give a false positive for another category of drug. [1]

In immunology

In immunology, 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 cross-immunity or cross-protective immunity, [2] although cross-reactivity does not necessarily confer cross-protection. In some cases, the cross-reactivity can be destructive, and immune response to one pathogen can interfere with or lower the immune response to a different pathogen.

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.

Cross reactivity has implications for flu vaccination because of the large number of strains of flu, as antigens produced in response to one strain may confer protection to different strains. [3] Cross-reactivity need not be between closely related viruses, however; for example, there is cross-reactivity between influenza virus-specific CD8+ T cells and hepatitis C virus antigens. [4]

Allergies

Cross reactivity may also occur between a pathogen and a protein found on a non-pathogen (i.e. food.) There may even be cross reactivity between two non-pathogens; [5] for example, Hevein-like protein domains are a possible cause for allergen cross-reactivity between latex and banana. [6]

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. [7] As CCDs apparently do not elicit allergic symptoms, a positive in vitro test based on IgE binding to CCDs must be rated as false positive.

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.

A radioallergosorbent test (RAST) is a blood test using radioimmunoassay test to detect specific IgE antibodies in order to determine the substances a subject is allergic to. This is different from a skin allergy test, which determines allergy by the reaction of a person's skin to different substances.

<span class="mw-page-title-main">Immunoglobulin G</span> Antibody isotype

Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

Haptens are small molecules that elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself. The mechanisms of absence of immune response may vary and involve complex immunological interactions, but can include absent or insufficient co-stimulatory signals from antigen-presenting cells.

<span class="mw-page-title-main">Latex allergy</span> Medical condition

Latex allergy is a medical term encompassing a range of allergic reactions to the proteins present in natural rubber latex. It generally develops after repeated exposure to products containing natural rubber latex. When latex-containing medical devices or supplies come in contact with mucous membranes, the membranes may absorb latex proteins. In some susceptible people, the immune system produces antibodies that react immunologically with these antigenic proteins. Many items contain or are made from natural rubber, including shoe soles, pen grips, hot water bottles, elastic bands, rubber gloves, condoms, baby-bottle nipples, and balloons; consequently, there are many possible routes of exposure that may trigger a reaction. People with latex allergies may also have or develop allergic reactions to some fruits, such as bananas.

In academia, computational immunology is a field of science that encompasses high-throughput genomic and bioinformatics approaches to immunology. The field's main aim is to convert immunological data into computational problems, solve these problems using mathematical and computational approaches and then convert these results into immunologically meaningful interpretations.

Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:

Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of several peptide sequences which can be both foreign and self in nature, just a few crucial residues can activate a single antibody or TCR. This highlights the importance of structural homology in the theory of molecular mimicry. Upon activation, these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity). Molecular mimicry is one of several ways in which autoimmunity can be evoked. A molecular mimicking event is more than an epiphenomenon despite its low probability, and these events have serious implications in the onset of many human autoimmune disorders.

<span class="mw-page-title-main">Polyclonal B cell response</span> Immune response by adaptive immune system

Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell.

A latex fixation test, also called a latex agglutination assay or test, is an assay used clinically in the identification and typing of many important microorganisms. These tests use the patient's antigen-antibody immune response. This response occurs when the body detects a pathogen and forms an antibody specific to an identified antigen present on the surface of the pathogen.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">Pro-hevein</span>

Pro-hevein is a wound-induced and a lectin-like protein from Hevea brasiliensis where it is involved in the coagulation of latex.

Immunomics is the study of immune system regulation and response to pathogens using genome-wide approaches. With the rise of genomic and proteomic technologies, scientists have been able to visualize biological networks and infer interrelationships between genes and/or proteins; recently, these technologies have been used to help better understand how the immune system functions and how it is regulated. Two thirds of the genome is active in one or more immune cell types and less than 1% of genes are uniquely expressed in a given type of cell. Therefore, it is critical that the expression patterns of these immune cell types be deciphered in the context of a network, and not as an individual, so that their roles be correctly characterized and related to one another. Defects of the immune system such as autoimmune diseases, immunodeficiency, and malignancies can benefit from genomic insights on pathological processes. For example, analyzing the systematic variation of gene expression can relate these patterns with specific diseases and gene networks important for immune functions.

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced. That is, despite multiple allelic variations of MHC molecules and multiple peptides presented on antigen presenting cells, the immune response is skewed to only specific combinations of the two. Immunodominance is evident for both antibody-mediated immunity and cell-mediated immunity. Epitopes that are not targeted or targeted to a lower degree during an immune response are known as subdominant epitopes. The impact of immunodominance is immunodomination, where immunodominant epitopes will curtail immune responses against non-dominant epitopes. Antigen-presenting cells such as dendritic cells, can have up to six different types of MHC molecules for antigen presentation. There is a potential for generation of hundreds to thousands of different peptides from the proteins of pathogens. Yet, the effector cell population that is reactive against the pathogen is dominated by cells that recognize only a certain class of MHC bound to only certain pathogen-derived peptides presented by that MHC class. Antigens from a particular pathogen can be of variable immunogenicity, with the antigen that stimulates the strongest response being the immunodominant one. The different levels of immunogenicity amongst antigens forms what is known as dominance hierarchy.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

Antigen-antibody interaction, or antigen-antibody reaction, is a specific chemical interaction between antibodies produced by B cells of the white blood cells and antigens during immune reaction. The antigens and antibodies combine by a process called agglutination. It is the fundamental reaction in the body by which the body is protected from complex foreign molecules, such as pathogens and their chemical toxins. In the blood, the antigens are specifically and with high affinity bound by antibodies to form an antigen-antibody complex. The immune complex is then transported to cellular systems where it can be destroyed or deactivated.

Cross-reactive carbohydrate determinants (CCDs) play a role in the context of allergy diagnosis. The terms CCD or CCDs describe protein-linked carbohydrate structures responsible for the phenomenon of cross-reactivity of sera from allergic patients towards a wide range of allergens from plants and insects. In serum-based allergy diagnosis, antibodies of the IgE class directed against CCDs therefore give the impression of polysensitization. Anti-CCD IgE, however, does not seem to elicit clinical symptoms. Diagnostic results caused by CCDs are therefore regarded as false positives.

References

  1. ↑ Saitman A, Park HD, Fitzgerald RL (September 2014). "False-positive interferences of common urine drug screen immunoassays: a review". Journal of Analytical Toxicology. 38 (7): 387–96. doi: 10.1093/jat/bku075 . PMID   24986836.
  2. ↑ Porrozzi R, Teva A, Amaral VF, Santos da Costa MV, Grimaldi G (September 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. doi: 10.4269/ajtmh.2004.71.297 . PMID   15381810.
  3. ↑ Mandelboim M, Bromberg M, Sherbany H, Zucker I, Yaary K, Bassal R, et al. (June 2014). "Significant cross reactive antibodies to influenza virus in adults and children during a period of marked antigenic drift". BMC Infectious Diseases. 14: 346. doi: 10.1186/1471-2334-14-346 . PMC   4107950 . PMID   24950742.
  4. ↑ Kasprowicz V, Ward SM, Turner A, Grammatikos A, Nolan BE, Lewis-Ximenez L, Sharp C, Woodruff J, Fleming VM, Sims S, Walker BD, Sewell AK, Lauer GM, Klenerman P (March 2008). "Defining the directionality and quality of influenza virus-specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus". The Journal of Clinical Investigation. 118 (3): 1143–53. doi:10.1172/JCI33082. PMC   2214846 . PMID   18246203.
  5. ↑ Negi SS, Braun W (2017). "Cross-React: a new structural bioinformatics method for predicting allergen cross-reactivity". Bioinformatics. 33 (7): 1014–1020. doi: 10.1093/bioinformatics/btw767 . PMC   5860227 . PMID   28062447.
  6. ↑ Mikkola JH, Alenius H, Kalkkinen N, Turjanmaa K, Palosuo T, Reunala T (December 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.
  7. ↑ Altmann F (2007). "The role of protein glycosylation in allergy". International Archives of Allergy and Immunology. 142 (2): 99–115. doi: 10.1159/000096114 . PMID   17033195.
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