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Abbreviations
Since the first appearance of life on earth about 4 billion years ago, protection has
been necessary against threats from the outside world (environment), but also from
interior self-derived cells and molecules. Homo sapiens, the most recent inhabitant
of this planet developed around 200,000 years ago and bears an evolutionary
optimized immune system to cope with all these environmental and self-derived
threats. As outlined in this book however, sometimes things go astray.
Microbial Triggers in Autoimmunity, Severe Allergy, and Autoallergy 13
Autoallergy
Herpes simplex Staph.aureus Malazezzia furfur
Fillagrin
Mala s 13 ≈
Dc hThioredoxin
autoIgE
Ba
Th1/17 Th2
B
memory
Exacerbation Autoallergy
Fig. 1 Viruses, bacteriae and fungi can elicit autoreactive TH1/17 or TH2 biased immune
responses. In case of autoallergy, either de novo autosensitization or cross-sensitization to exog-
enous, microbe-derived allergens can trigger B cell responses with autoreactive IgE or
autoreactive T cells
Physical barriers form the first line of defence against biological external threats,
such as bacteria or viruses, and include the skin but also mucous membranes of the
lung, gut, and genitalia. The rapid-acting innate immune system with key players
such as macrophages, neutrophils, NK cells and the complement system forms a
second line of defence. Finally, the adaptive immune system constitutes the third
line of defence, consisting of B cells and plasma cells, which produce antibodies
(IgA, IgD, IgE, IgG, and IgM), and T cells, which target infection or tumour cells.
The innate system reacts quickly within minutes but with little specificity. It is a
short-term system without memory. In contrast, the adaptive immune system reacts
slower (within days to weeks), but is highly specific and develops long-lasting
memory. Both systems tackle invaders from outside (e.g. infection) or inside
(e.g. cancer), but it is the adaptive immune system that leads in some individuals
to allergy (‘outside, foreign’) or autoimmunity (‘inside, self’). It is hypothesized
that allergy can be complicated by autoimmunity in chronicity and severity,
so-called “autoallergy” (Fig. 1). Indeed, allergy and autoimmunity share common
features. Prevalence of both disease states have been rising over the last decades
(allergy 25% versus 7% in autoimmunity). Allergy and Autoimmunity are charac-
terized by T- and B cell reactions against harmless foreign proteins (allergy) or
harmless self-proteins (autoimmunity), and both share similar genetic
14 F.M.S. Badloe et al.
is dominated by a T cell clone that has been derived from a previous disease flare by
epitope spreading (Ercolini and Miller 2009).
There is a large number of bacteria, viruses, and fungi that can trigger autoimmune
disorders or that are involved in their pathogenesis. The most important will be
discussed below (Table 1).
Molecular mimicry of Helicobacter pylori (H. pylori) can induce gastric autoim-
munity (Smyk et al. 2014; Hasni 2012). In autoimmune type A-gastritis for exam-
ple, H. pylori infection leads to activation of gastric CD4+ T cells that recognize
cross-reactive epitopes shared by H. pylori and the human gastric H+, K+-ATPase
(D’Elios et al. 2004).
Campylobacter jejuni (C. Jejuni) is associated with the development of Guillain-
Barré syndrome (GBS). Lipopolysaccharide (LPS) on the outer layer of the
C. jejuni serotype (O:4 and O:19) bacteria structurally mimics the human gangli-
oside (GM1 and GD1a) (Ercolini and Miller 2009). Similar to C. jejuni,
Haemophilus influenzae infection can induce antibodies to LPS that are cross-
reactive with human ganglioside (GM1) in neural tissue. The presence of a
ganglioside-like structure on its LPS suggests that molecular mimicry may play a
role in the induction of GBS (Ercolini and Miller 2009; Mori et al. 2000).
Table 2 Microbial triggers and mechanisms of action in atopic dermatitis and allergic asthma
Atopic dermatitis Allergic asthma
Bacterial
Staphylococcus Upregulation IL-17 expression TH2 response
epidermidis
Staphylococcus Enterotoxins superantigens
aureus T-cell mediated inflammation
MRSA Higher number of superantigens
Mycoplasma Induction of TH2 cyto-
pneumoniae kines, IgE production
Haemophilus TH2 response
influenzae
Viral
Herpes simplex α-toxin
virus
Vaccinia virus α-toxin
Respiratory TH2 response
syncytial virus
Human IL-33, TSLP, and IL-25.
rhinovirus TH2 response
Influenza virus TH2 response
Yeast
Malassezia spp. MnSOD cross-reactivity, auto-reactive T-cells,
Histamine release, Cytokines, IgE antibodies
MRSA methicillin-resistant Staphylococcus aureus, TSLP thymic stromal lymphopoietin, MnSOD
manganese superoxide dismutase
3.1.1 Staphylococci
3.1.3 Fungi
Malassezia Species
The interaction between multiple Malassezia species and the immune system is
linked to skin inflammation in AD. Malassezia sympodialis allergens Mala s
Microbial Triggers in Autoimmunity, Severe Allergy, and Autoallergy 19
Following food allergies with or without AD, asthma is the second manifestation of
the atopic march. Episodic wheeze occurs in about 30% of all children, while
persistent asthma occurs in about 10% of all children and 5% of adults (Thomsen
2015). Asthma was already described in ancient Egyptian times and probably
before that. The Georg Ebers Papyrus, discovered in Egypt in the 1870s, contains
prescriptions written in hieroglyphics for over 700 remedies (Wahn 2014). One of
the ancient Egyptian remedies was to heat a mixture of herbs on bricks and inhale
their fumes. The term Asthma is delineated from the Greek verb “aazein,” to pant
or to exhale with the open mouth. It is first mentioned in The Iliad (Homerus), about
the siege of Troy. As a medical term, it was already used by Hippocrates in the
Corpus Hippocraticum, but it could have been both a clinical entity, or a symptom.
At the present time however, asthma is considered a heterogeneous disease with
different endotypes: early-onset allergic asthma, adult-onset (severe) eosinophilic
asthma, late onset TH2 asthma, late-onset non-allergic asthma of the elderly, virus-
induced asthma, exercise induced asthma, obesity-related asthma, non-eosinophilic
asthma, brittle asthma, menstrual-linked asthma, and smoking associated asthma
(Koczulla et al. 2017). This deliberate endotyping of asthma compared to AD
allows the development of tailored guidelines and treatment approaches. Valid
biomarkers would be extremely helpful keys to disease endotyping and pose a
current research topic (Chaker et al. 2017; Zissler et al. 2016). This paragraph will
review the mechanism of microbial triggers in allergic asthma (see Table 2).
Several bacteria have been linked to the exacerbation of asthma (Earl et al. 2015;
Lan et al. 2016; Green et al. 2014; Papadopoulos et al. 2011; Guilbert and Denlinger
20 F.M.S. Badloe et al.
Respiratory syncytial virus (RSV), human rhinovirus (HRV), and influenza virus
(IFV) in infancy are associated with the development of allergic asthma and are
major causes of asthma exacerbation (Busse et al. 2010; Iikura et al. 2015; Pelaia
et al. 2006). RSV, HRV, and IFV may cause asthma exacerbation due to their
induction of epithelial cell-derived alarmines such as IL-33, thymic stromal
lymphopoietin (TSLP), and IL-25. These cytokines are strong inducers of type-2
immune responses via innate lymphoid type 2 and dendritic cells (Lan et al. 2016;
Beale et al. 2014).
An especially difficult to treat population are patients with chronic and severe
AD. Already in 1926 Van Leeuwen et al. raised the theory that auto-sensitivity
against human skin dander plays a role in atopic patients. These findings were
reproduced by Hampton and Cooke in the 1940s and since the late 1990s Valenta
and others demonstrated the presence of autoreactive (auto)-IgE in the sera of AD
patients. Auto-IgE titers correlate with AD severity (Natter et al. 1998; Valenta
et al. 1998). It was postulated that IgE-autosensitisation and autoreactive T cells can
perpetuate and aggravate AD via autoimmune inflammation and such an
“autoallergy” might constitute a novel endotype of AD (Bieber et al. 2017;
Hradetzky et al. 2015) (Fig. 2).
Thus, the term “autoallergy” describes an autoimmune process accompanying
atopic dermatitis, with auto-reactive IgE as a hallmark (see Table 3). Microbial
factors are suspected as trigger factors, including IgE-cross-reactivity of human
Manganese superoxide dismutase (MnSOD) or Thioredoxin with IgE directed
against the respective homologue proteins derived from Aspergillus fumigatus
and M. sympodialis (Hom s 2 and Hom s 3) (Hradetzky et al. 2015; Schmid-
Grendelmeier et al. 2005; Crameri et al. 1996; Balaji et al. 2011). The mechanism
of molecular mimicry and cross-reactivity between human and microbial proteins
were described in the previous section. Moreover, a cellular TH1 immune response
plus an IL17/IL22-dominated immune response can be elicited by Hom s 2. In the
context of inflammation and itch, auto-allergens may be continuously released from
Microbial Triggers in Autoimmunity, Severe Allergy, and Autoallergy 21
Allergens Allergens
Selfantigens
FcεR
MC
FcεR FcεR
MC B Th2 MC B Th2
Fig. 2 Vicious cycle of autoallergy. The auto-allergen may replace the need for allergens to
drive tissue inflammation and convert seasonal allergies into chronic disorders. Left panel: in
non-atopic healthy subjects, allergens are phagocytised by Langerhans cells (a dendritic cell subset
located in the epidermis), and a regulatory T cell response is induced in the draining lymph nodes,
inhibiting allergic TH2 sensitization. Middle panel: in patients suffering from seasonal atopic
diseases, a lack of regulatory T cell response leads to the formation of allergen-specific TH2 cells
and plasma cells that produce allergen-specific IgE-molecules. Because self-antigens are presented
under inflammatory conditions, auto-IgE can be induced. Right panel: in autosensitized patients,
autoallergy with self-antigen-specific IgE and TH1/TH2 cells maintain inflammation, which
is constantly triggered by the traumatic release of self-antigens via scratching (Picture courtesy
of C. Schmidt-Weber)
the skin cells, such as keratinocytes and fibroblasts, by scratching or wounding and
thereby maintaining a vicious autoallergic cycle of inflammation in autoallergic AD
(Hradetzky et al. 2015; Mittermann et al. 2008).
5 Conclusion
Severe reactions in allergic asthma and the type 2 dominated inflammation in atopic
dermatitis can be triggered or aggravated by multiple microbial factors, including
bacteria, viruses, and fungi. Of special concern is S. aureus, which is of significant
importance in AD and allergic asthma, especially strains of MRSA. In asthma the
aggravating impact of multiple bacteria and viruses is well-documented, and in
atopic dermatitis viral complications can be life threatening, such as eczema
herpecticum. In head-and-neck eczema the colonization with malassezia furfur is
a therapeutic target. In autoimmunity, microbial infections can be the starting point
for the development of disease by various molecular pathways, including mainly
molecular mimicry or bystander activation. Here frequent pathogens, such as EBV
and Coxsackie viruses can induce the pathophysiologic catastrophy of “break of
self tolerance.” Current research is geared towards detection of protective microbial
species and the physiologic time window of commensal microbial colonization.
Adequate anti-microbial therapies and prevention strategies thus are important for
prevention or amelioration of allergic- and autoimmune diseases. Finally, it is
hypothesized that autoallergy could initially be initiated by mechanisms such as
molecular mimicry and may thereby lead into a chronic disorder that has become
secondarily allergen independent. Here again fungal malassezia species are
suspected as elicting pathogens. Taken together, microbes of all classes, bacteria,
viruses and fungi, have a strong impact in severe allergic disease and therefore need
to be considered as targets in prevention and therapy of allergic diseases. Future
research needs to address beneficial and harmful effects of microbes in the origi-
nation, elicitation and chronification of severe allergic conditions.
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