Table 2 Background for architects and building engineers: basic concepts of the hygiene, microbial biodiversity (inclusive of bacteria, fungi, protists, and viruses), and food epitope hypotheses

Interdisciplinary work—in this case, between architects, building engineers, and microbiologists—requires extra effort for clear communication. This table contains some background for the hygiene-microbial biodiversity hypothesis and the food epitope alternative proposed in the text. A caveat: “When you teach you are lying all the time. Of course at advanced levels you are lying a lot less but you are still lying all the time.” [75].

Specific molecules have specific shapes and specific molecules recognize each other by their complementary shapes. The fitting together of complementary shapes is analogous to a lock and its key. Specificity based on matching complementary molecular shapes is a foundational and central idea in molecular biology [76].

Many but not all molecular recognition epitopes are based on proteins. Proteins are comprised of combinations of 20 amino acids. The specific shape of a protein molecule depends on its amino acid sequence as specified by the DNA sequence of its gene. In this context, a different allele of the same gene has a slightly different DNA sequence that encodes a slightly different amino acid sequence that in turn leads to a protein that is slightly different [77]. For example, the same antibody might recognize a protein encoded by a different allele but the binding may have subtly altered kinetics.

The part of a molecule that is complementary to another molecule is called an epitope. Molecules specifically recognize each other if, and only if, they have complementary epitopes. Most human proteins are encoded by the DNA sequence of genes received from the gametes of the parents but immune system proteins are different: they are encoded by new alleles of immune system genes that continue to be generated in adult life. (Non-protein epitopes and variation in their shapes are of great biological interest and importance but are less understood and even harder to explain.)

Antibody-encoding and T cell receptor (immune system) genes are selected by the epitopes they are exposed to. The number and type of different epitopes that the immune system is exposed to has important and only partially understood consequences for the entire organism’s resistance to infection and probability of autoimmune disease. The hygiene hypothesis and biodiversity hypotheses propose that exposure to a diverse set of microbial epitopes aids healthy immune system development and function.

An apt metaphor for the hygiene and biodiversity hypotheses is found in the poetic lines “A lot of people don’t have much food on their table/But they got a lot of forks’n’ knives/And they gotta cut somethin” [78]. The relevance of this poetic metaphor is the specific hypothesis that if the immune system does not experience a diverse and appropriate set of epitopes from microbes and/or food, then it is more likely to inappropriately target epitopes of self and thereby predispose to autoimmune and hypersensitivity syndromes.

The consensus sequence is a single sequence and encodes a single epitope. In a population of genes, some have a slightly different sequence, these are called different alleles of the same gene, and some encode slightly different proteins with different epitopes. The population of alleles forms a “cloud” or “quasispecies” around the consensus sequence.

In the food epitope hypothesis, the role that the hygiene or biodiversity hypotheses assign to microbial epitope diversity is partially assigned to food epitope diversity in the food is in turn a function of allelic diversity in the food crops.

Different uses of the word “epitope” can lead to confusion: (a) “Near epitopes” differ in small ways that allow them to be bound to the same antibodies and/or T or B cell receptors but with different kinetics and (b) “far epitopes” which are different parts of the antigen. If the antigen is a protein, “near epitopes” might represent adjacent and near-adjacent amino acids, whereas “far epitopes” would be distinct peptides that can be completely separated and shown to bind to independently with minimum cross-reactivity. Most immunological literature does not distinguish very well between “near” and “far” epitopes. An authors’ meaning has to be derived from usage. Examples of “far” epitopes are found in the characterization of a stereotyped set of epitopes characterized by neonatal antibodies [79], as well as omics surveys of the antibody [80] and T/B cell receptor repertoires [81]. The meaning of the word “near” epitope is evident in papers on viral quasispecies and immune evasion [82]. The food epitope hypothesis is that consuming a population of “near” epitopes in food promotes development and maintenance of a more healthful immune system.