The objective of this study was to determine which of two alternative models best accounts for expressions of allergen-specific IgE immune system outcomes in families with significant histories of atopic diseases. One model, Obligate Inheritance, postulates that there are specific inherited genetic alterations resulting in abnormal recognition and /or response to allergens that would directly influence the expression levels of quantitative IgE traits. If correct, then there should be significant correlations of IgE trait expression levels among members of kinships, as these presumed genetic alterations would be passed on within families.
The alternate model, Stochastic Bias, proposes that the immune regulatory pathways are the same for everyone, but temporary changes in physiological status may ‘skew’ these responses resulting in ‘errors’ in recognition/response leading to a pathological outcome. In this case, underlying regulatory pathways may temporarily ‘skew’ an individual’s humoral response. Although the likelihood of an atopic immune response may be inherited, the allergen-specific IgE responses are random variables unrelated to outcomes expressed by their relatives. The results favor this Stochastic Bias model.
Atopic, IgE-mediated disorders are common chronic human diseases that presumably arise from inherited errors in immune system recognition and/or response to otherwise benign, non-infectious environmental antigens (allergens). Results of numerous genome screens and case-control studies show that multiple genetic elements contribute to these conditions (Hoffjan et al, 2003
). However, regardless of the number of genetic alterations that may be involved, the underlying mechanisms cannot be accounted for by simple Mendelian inheritance that directly or indirectly imply a causal physiological linkage between stimulus (allergen exposure/recognition) and response (humoral immune development). Results presented here and in previous studies argue strongly against this likelihood.
Evidence that the atopic disorders are inherited derives primarily from epidemiological studies: (1) these conditions tend to ‘cluster’ within families, (2) there is a higher concordance of atopic outcomes among identical (monozygotic) twins compared to fraternal (dizygotic) twins and (3) the concordance of atopic responses is higher among first-degree relatives (parent-child or sibling-sibling) than in other pedigree relationships (Blumenthal & Björkstén, 1999). But, epidemiological studies also show that there are large world-wide variations in atopy prevalence, being as low as < 5% of the populations in less-developed countries, to as high as 25–40% of the populations in highly industrialized countries (ISAAC, 1998
). Current consensus holds that IgE-mediated atopic conditions are inherited, but that they can be significantly modulated by random environmental contingencies. Unfortunately, these observations do not address the nature of immune system responses to these environmental challenges.
Epidemiological studies, or most studies related to the biology of these conditions, have focused solely upon the adverse immune manifestation of allergen-specific IgE. However, especially in the cases of the common aeroallergens, like ragweed pollen or house dust mites that initiate immune responses within the respiratory tract, specific IgE production is only one manifestation of immune response. In fact, most (all) people will mount a response to aeroallergens involving any or all of the IgA and IgG classes or subclasses (Batard et al 1993a
; Jackola et al, 2002
). It is only among those with an inherited atopic tendency that one also finds a specific IgE response. Yet this is not absolute, as it has been shown in the earliest years of life that production of allergen-specific IgE is common, at least up to the age of two years (Hattevig et al, 1993
). A distinction arises in that among children who do not develop atopy this phenomenon is transient, while in children who do develop atopy the phenomenon is persistent. Atopic disorders involve a developmental progression (the so-called “atopic march”).
Two key determinants in whether or not an atopic, allergen-specific IgE will arise involves the likelihood (probability) of an isotype switch to IgE and the relative ‘vigor’ of this response based upon the binding affinity of the antibody for the allergen that induced its production. We have shown that the atopic response is characterized by an extremely high binding affinity by IgE for allergen(s) (Pierson et al, 1998
; Pierson-Mullany et al, 2000
). We have also found that atopy involves not only a high affinity IgE response, but an attenuated, low binding affinity IgG1 response, whereas a non-atopic response evolves to a high affinity IgG1 response that is equal in ‘vigor’ to the high affinity atopic IgE (Jackola et al, 2002
). This study suggested that there is a ‘selective competition’ among antibody isotypes akin to Darwinian evolution on a microscopic scale, in which different “species” (antibody isotypes) “compete” for a common “resource” (allergen). Both allergen-specific isotypes may co-exist, but the one with the “selective advantage” (highest binding affinity) will dominate.
Further, in the earliest years of life (newborn to 6 years), the developmental “trajectories” of high affinity atopic IgE and high affinity non-atopic IgG1 are comparable (Jackola et al, 2005
). Taken together, these results suggest that the difference between an atopic and a non-atopic response to the same allergen(s) is due to (1) the likelihood of switching to a particular isotype, (2) how vigorous this ‘isotype choice’ is and, most importantly, (3) atopic IgE may only be an ‘error’ in isotype switching during an otherwise normal process of antigen recognition and humoral response evolution.
The induction of the characteristic wheal and flare reaction in the percutaneous skin prick test (SPT) is evidence for the production of high binding affinity, allergen-specific IgE (Pierson-Mullany et al, 2002
). and of the current report show that the number, N, of SPT [+] results for any person is a random variable. And, this number reflects the induction of unique clones of lymphoid cells that produce these vigorous IgE responses to one or more allergens. We have previously shown that the specific allergens to which people become atopically sensitized are random variables independent of ant sensitivity “patterns” within families (Jackola et al, 2004a
Also, from our previous experimental work (Jackola et al, 2002
), in contrast, among those people who are not atopically sensitized to some of the allergens used in this battery, they are with high probability producing a vigorous IgG1 response that does not involve a clinical manifestation. The allergens used in this screen are widely distributed in this geographic locale, and the results presented here are from families who with high likelihood share similar environmental conditions, including the allergens to which they are exposed. Thus, lack of a clinical response manifestation (SPT [+] result) is not due to lack of exposure to these allergens.
also points to another contingency involved with the likelihood or not of an atopic IgE switch. Among those people who have any SPT [+] result, but who differ with regard to the presence or absence of asthma, the numbers of allergens to which they are sensitized are random variables, approximated by exponential probability distributions. The difference is that those with asthma have a higher probability of producing IgE to more allergens than those without asthma. These results are not unique to this study population. Epidemiological studies have also observed these exponential distributions; as for example in Pearce et al (1999)
, a comprehensive review of the epidemiological literature relevant to atopic disease, and the large United States health survey NHANES III ( in Arbes et al, 2005
By diagnostic criteria, asthma is a chronic inflammation of the airways. This inflammation in large part involves components of the mucosal immune system that are prone to develop germinal center-like foci (so-called mucous associated lymphoid tissue, or MALT), akin for example to Peyer’s Patches in the gut, that can be involved in immunoglobulin production and isotype class switching. These foci are a common feature of chronic inflammatory diseases of the immune system, such as autoimmune disorders (Aloisi & Pujoll-Borrell, 2006
). It has been suggested that they are also involved in the atopic disorders, including atopic asthma (reviewed in Gould et al, 2006
). References in this review show that only among people with an inherited propensity for atopy will IgE be found in these foci. Non-atopics produce either IgA or IgG in these foci, if any detectable response is present.
Whether or not these foci make significant contributions to atopic disease is controversial. But, they highlight the importance of germinal center (GC) reactions in “decision making” in the evolution of a humoral response to antigens. Current consensus on GC reactions proposes that there are at least three critical checkpoints in formation of an antigen-specific response (Lindhout et al, 1997
; Tarlinton & Smith, 2000
): (1) Antigen-specific initiation of the GC reaction, (2) Selection of the best-fitting B cell receptor (BCR) by follicular dendritic cells (FDC’s) and (3) Antigen-dependent, T-cell-mediated isotype switching. Factors that promote antigen retention by FDC’s and induce the most vigorous (highest affinity) BCR also promote the probability of isotype switching, especially to IgE; antigen retention and the overall “intensity” of the GC reaction make significant contributions to what antibody isotype will predominate.
The importance of the total time in the GC reactions for isotype switching has been given support from in vitro
studies of isotype switching by initially IgM+ expressing B cells (Tangye et al, 2002; Hasbold et al, 2004). Given the appropriate stimuli and co-factors, these cells will progress through several rounds of the cell division cycle (CDC) prior to switching to IgG. In fact, this group has shown that the total umber of CDC’s is critical for the initiation of class switching to IgG. An additional number of CDC rounds are also required before an IgE switch is detected. Whether or not this involves a sequential mechanism, like IgM → IgG → IgE, by the same cells is not known. An alternative is that some IgM cells can switch directly to IgE, and by-pass the IgG switch (saltatory switch), which is supported by a murine model (Jung et al, 1994
). In either case, these results show that switching to IgE is less common than switching to IgG, and requires more total time for lymphoid cells to make this switch decision.
The in vitro
studies also highlight another important feature of immune system “decision making”; at the cellular level, metabolic decisions between alternate pathways are stochastic in nature rather than strictly deterministic (Hasbold et al, 2004). Indeed, it has been argued that these stochastic mechanisms are the rule rather than the exception in most immunological information processing at the cellular/molecular level, as these mechanisms promote response plasticity and the fidelity of developing a robust response to highly variable and unpredictable environmental circumstances (Germain, 2001
Among some of these stochastic networks is the well-known CD28/ICOS/CTLA4 family of co-factors that promote interactions between T cells and antigen-presenting cells (APC) or B cells (Green, 2000). Both CD28 and CTLA4 bind to the same counter receptors on APC’s or B cells, B7.1 (CD80) and B7.2 (CD86), but they differ in function. CD28 is an amplifying cofactor, while CTLA4 is an inhibiting co-factor. The Inducible Co-factor of Stimulation (ICOS) apparently modulates the activities of the other two. Taken together, this family describes a classic network involving feedback regulation (Jansson et al, 2005
). The relative strength and duration of the countervailing co-factors’ interactions will determine the final response, which is not absolute but contingent upon the interplay of these elements. In fact, studied separately, both CTLA4 (Hizawa et al, 2001
) and ICOS (Shilling et al, 2005
) have been implicated in atopic IgE production.
Regardless of the specific network or metabolic system(s), the overall effect is variability in possible responses, and not deterministic regulation. Genetic alterations in some element(s) of a network, like a feedback loop, may alter the probability of one outcome as opposed to another, but this is not deterministic; it is stochastic. If the evolution of immune responses, such as the development of allergen-specific IgE atopy, was strictly deterministic and under the control of some finite number of genes, then there would be significant correlations in the expression levels of quantitative traits among genetically similar people, such as parent-child or sibling-sibling kinships. Yet, as shown in this study, we can find no evidence for this based upon large numbers of atopically sensitized people from numerous families with history of these diseases. This rules out Obligate Inheritance of allergen-specific IgE-mediated disorders.
The alternative is that a model describing Stochastic Bias is in force. Again, it is most likely that all people share the same metabolic pathways and networks contributing to the development of humoral immune responses to common non-infectious allergens. But, temporary physiological biases may ‘skew’ the responses among some people and lead to a pathological outcome as an alternative to an otherwise normal process of antigen recognition and immune response development. In this model, inheritance plays a role of one among several factors that contributes to skewing a response.
In this light, specific IgE production is not a cause of atopic disorders, it is a consequence of them. As it is most likely that people from families with history of these diseases will develop an atopic immune response to some number of allergens, what is inherited is the likelihood of atopy but not the specific manifestation. Future gene searches for these complex diseases should focus upon elements that increase the likelihood of these adverse responses, and not the specific responses themselves.