Autoimmune Diseases and Inflammatory Disorders of Unknown Etiology; Contemplating Causation and Implication in Public Health Protection- Juniper Publishers
Juniper Publishers- Journal of cell Science
Abstract
Due to their multi factorial causation, the
investigation of the etiology of autoimmune and inflammatory disorders
constitutes a challenge that seems to exceed greatly that which was
faced by the pioneers of the previous centuries, in connection with
microbial diseases. Genetic factors, microbial pathogens, the alteration
of the normal microbial flora and/or of the micro biome have been
implicated to the etiology of the specific category of diseases but
their interaction is so complex that the distinction of the causal from
those that are incidental becomes extremely difficult. This issue is
further complicated by food additives that are nowadays widely used and
could have a contributing role to the pathogenesis of disorders
associated with immune dysregulation. In this respect, it is perhaps
critical that administrative authorities involved in public health
protection revised their licensing strategy from deciding based on
evidences of harmfulness, to taking seriously into consideration even
indications of the latter or requiring proof of safety.
Keywords: Autoimmune
diseases; Inflammatory disorders; Causation; Etiology; Erythritol;
Arabinogalactan; Mycobacteria; Paratuberculosis; Crohn’s diseaseAbbreviations: ARPs: Antigen Recognition Patterns
Introduction
In ancient Greece, the notion of infectious agents
was depicted with the term “miasma” that was used to indicate any factor
resulting to bodily, spiritual or ethical deviation from normal. In
1665, Robert Hooke published his book titled “Micrographia”, in which he
provided a detailed description of the structure of a simple microscope
that was invented many years before (1590), by Zacharias Janssen. This
was an event of fundamental significance in the investigation of disease
etiology and motivated several inspired researchers, such as Anton van
Leeuwenhoek who provided the first physical proof of microscopic
organisms in 1670, and Robert Koch with his landmark publication of the
Koch’s postulates in 1890. The latter constituted a concrete context
that formulated the research conducted on all aspects of the
investigation of disease etiology, for several decades. The idea was
simple and common for all infectious diseases: a pathogen transmitted to
a sensitive host causes a specific disease; the pathogen should not be
detected in healthy individuals; a sensitive host exposed to the
pathogen should develop the specific disease. These postulates proved
efficient in connection with a large number of infectious
diseases and triggered the developments towards their accurate
diagnosis, treatment, control and in several cases, eradication.
However how does the scientific community respond
today to the challenge represented by the dramatic rise in autoimmune
and inflammatory disorders? If the elementary technological developments
of the 17th century proved sufficient to clarify disease pathogenesis
of so many infectious diseases in just over a century, how is it
possible that in spite the revolutionary discoveries of the 20th
century, a large number of wide spread diseases continues to be of
unknown etiology? Is public health protection a parameter that should be
considered in connection with the specific diseases or at least with
those that appear to be potentially infectious, i.e. associated in many,
but not all cases with exposure to one or more pathogens?
In contemplating the causation of autoimmune diseases
and inflammatory disorders of unknown etiology, the logical approach
would be to follow a course similar with that of Koch, and attempt to
define first the notions of “disease” and “sensitive host”; exactly
therein lies today the real challenge. Regarding case definition, what
appears to be a single disease entity often proves to have specific
forms that are similar in terms of clinical
manifestation but different with regards to etiology. A typical
example of the latter that was not as obvious a few years ago
is cancer, a pathologic condition that is no longer perceived as
a single disease and can be manifested by many similar forms,
triggered by etiologic factors that are remarkably different such
as viruses, chemicals, radiation etc. With regards to the definition
of the sensitive host, the difficulty lies in that susceptibility does
not apply at, but within the level of animal species, depending
on various parameters including age, gender, race and genetic
predisposition. The latter is neither precise nor definite i.e.
there are many different factors possibly resulting to similar
types of genetic predisposition and this can be influenced in the
course of life by various parameters including stress, nutrition,
alteration of the constitution of normal microbial flora, genetic
and epigenetic factors. An example of a disease that seems to
fit perfectly in the specific context of pathogenesis is Crohn’s
disease.
Crohn’s disease is a form of chronic eleocolitis that affects
humans with substantial negative impact to their quality of life
[1]. Though the disease is still officially considered of unknown
etiology, it is rather clear that the basis of its pathogenesis is
immune dysregulation. Several factors have been proposed
as relevant, such as genetic predisposition, nutrition, stress,
the alteration of the microbial flora and/or of the microbiome,
and various microbial organisms [2]. In connection with the
latter, reference is more commonly made to Mycobacterium
avium subsp. paratuberculosis (MAP) [2]. Notably MAP, which
is wide spread in nature and many types of food, is the cause
of paratuberculosis that affects the intestine primarily of
ruminants, causing lesions that are very similar with those of
Crohn’s disease. It has been suggested that the implication of
mycobacteria in this and other diseases of unknown etiology,
such as sarcoidosis, is associated with the regulatory role they
acquired in the process of the evolutionary development of the
mammalian immune system, formulating its response to various
antigen recognition patterns (ARPs), and its ability to selectively
react or tolerate similar antigenic stimuli [3,4].
This idea is the foundation based on which, a new approach
was made very recently for the treatment of Crohn’s disease
patients, using a vaccine that contains MAP [5]. However,
none of the factors mentioned above can be associated with
all cases of disease, and causal effect cannot be determined in
a definite manner for any of them, not even for a specific subset
of patients. This has generated speculations about disease
definition implying that maybe, just like cancer, Crohn’s disease
is a label that should be perceived as descriptive of a set of
conditions that are similar with regards to clinical manifestation
but distinct, in terms of etiology [2]. Unfortunately the issue of
Crohn’s disease causation is still very far from being resolved,
mainly because the aforementioned factors are so closely
interlinked that it becomes extremely difficult to differentiate
the causal from those that are incidental. This problem however
and the context of disease pathogenesis outlined here does not
apply only to Crohn’s disease. Some or all the factors associated
with the causation of the specific pathologic condition are being
identified as potentially significant for many others. To mention
only a few, sarcoidosis has been associated through several
reports with exposure of genetically predisposed individuals
to Propionibacterium acnes or certain Mycobacterium spp. [6];
human exposure to MAP has been associated in addition to
Crohn’s disease with multiple sclerosis, diabetes mellitus type I,
Hashimoto’s thyreoiditis, sarcoidosis, rheumatoid arthritis and
certain forms of cancer [2]; the alteration of the constitution of
microbial flora and/or of the microbiome has been linked to a
plethora of diseases of unknown etiology [4], the most recent
and rather unexpected addition to which is autism [6].
The overall context formulated today in connection with
diseases of unknown etiology would be incomplete without a
reference to the potential role of specific food additives, which
complicates even further the investigation of their pathogenesis.
Two of the most widely used products of this category that
could be implicated in the issue addressed here is erythritol
and arabinogalactan. The former is a polyol that exists in a
natural form in some fruits and vegetables but is used in an
artificial form as a low calorie food sweetener, since it is very
poorly metabolized by the intestinal and the oral microbial flora.
Arabinogalactan is a polysaccharide consisting of arabinose and
galactose, and can be found widely in nature, in plants and in
the cell wall of specific bacteria. Today, arabinogalactan is used
broadly as a chemical stabilizer in cosmetics, food and animal
feeds, and as an immune stimulating or drug delivery agent
in therapeutics and food supplements. Apparently due to the
wide use of erythritol and arabinogalactan, human exposure to
them exceeds greatly the natural, in terms both of intensity and
duration. This could constitute an element of key significance
in their role as potential or perhaps incidental pathogenic
factors for specific sub-sets of the human population who, for
various reasons, are prone to immune dysregulation. This
association should be primarily assessed within the context
of the microbial flora and secondarily in connection with the
immune response to ARPs that the mammalian immune system
has been trained to perceive as critical in terms of immune
regulation and responsiveness. Indeed regarding the former,
chronic exposure to erythritol is associated in many research
reports with functional alteration of the intestinal microbiome,
which may affect millions of consumers leading to autoimmune
diseases and inflammatory disorders [4,7,8]. Erythritol is also
a significant bioactive substance for potent bacterial pathogens.
In more detail, the specific inert under normal circumstances
sugar is identified as the factor that attracts Brucella abortus to
the genital tract of female bovines, leading to chronic infection
and abortion [9]. Erythritol has also been associated with
up regulation of specific pathogenic genes of other Brucella
spp., including Brucella melitensis, the main causal agent of
brucellosis of humans [10]. Arabinogalactan on the other hand is a major component of the cell wall mainly of mycobacteria,
nocardia and corynebacteria, and contributes significantly to
their ability to resist phagocytosis and to survive as intracellular
pathogens. In this respect the use of arabinogalactan as an
immune stimulating agent seems rather apparent at least for
normal individuals, but generates concern in connection with
the response that it could activate to those prone to immune
dysregulation, especially considering the strong indications
about the implication of mycobacteria in autoimmune diseases
and inflammatory disorders [2,3,4,6].
Conclusion
The multi factorial causation of autoimmune diseases and
inflammatory disorders that currently remain of unknown
etiology constitutes a challenge that seems to exceed greatly
that which was faced by the pioneers of the previous centuries,
in connection with microbial diseases. The progress is indeed
remarkable but there are no indications that the etiology of
the specific pathologic conditions will be clarified in the near
future. In this respect, it is nowadays perhaps critical that
administrative authorities involved in public health protection
revised their licensing strategy from deciding based on
evidences of harmfulness, to taking seriously into consideration
even indications of the latter or requiring proof of safety.
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