**1. Introduction**

Psoriasis (Ps) is a complex and heterogeneous disease that affects not only the skin of the patients but echoes also on several other organs [1]. Recognized as a chronic autoimmune inflammatory disease, mediated mainly by T cells, Ps has important systemic manifestation [2], being frequently associated with psychological, metabolic, arthritic and cardiovascular comorbidities. Ps associated pathologies can lead to increased mortality and alters the clinical management of the patients. Ps affects 0.5–1% of children and in the world's population the prevalence raises around 2–3%. Prevalence of Ps varies depending on age, sex, geography, ethnicity, genetic and environmental factors [3]. Although it can occur at any age, the most common cases are reported before the age of 35, an age range that affects highly active individuals [4].

The causes of Ps have not yet been fully elucidated. Besides genetic predisposition and environmental factors, an inefficient immune system is highly involved in Ps onset. Among the triggers or aggravating factors of Ps we can mention air pollutants and exposure

**Citation:** Surcel, M.; Munteanu, A.; Isvoranu, G.; Ibram, A.; Caruntu, C.; Constantin, C.; Neagu, M. Unconventional Therapy with IgY in a Psoriatic Mouse Model Targeting Gut Microbiome. *J. Pers. Med.* **2021**, *11*, 841. https://doi.org/10.3390/ jpm11090841

Academic Editor: Jun Fang

Received: 4 August 2021 Accepted: 25 August 2021 Published: 26 August 2021

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to sunlight, prolonged exposure to UV radiation [5], administration of certain drugs (βblockers, lithium) [6], smoking [7], obesity [8] and alcohol consumption [9]. Streptococcal infections, involved in both acute and chronic forms of the disease [10] and mental stress are also factors that have with critical roles in the initiation, development and exacerbation of Ps [11].

The assessment of Ps severity is mainly based on clinical indicators [12], but the golden standard remains the PASI score (Psoriasis Area Severity Index) [13], which combines the severity (erythema, scaling, induration) and the percentage of affected area.

19In Ps pathogenesis are involved both innate (NK cells, macrophages, dendritic cells) and adaptive immune cells (T lymphocytes), as well as non-immune cells (keratinocytes), their interactions being mediated by pro-inflammatory cytokines/chemokines that maintain the chronic inflammatory state [14,15]. Among the biological therapies currently available, TNF-α inhibitors [16–18], IL-23 inhibitors [19–22], IL-17 inhibitors [23–25] are the ones that entered the standard care of Ps. New treatments that address immune pathways and are currently undergoing clinical trials include RORγt inhibitors [26], IL-36 Receptor antagonist [27], Janus Kinase (JAK) inhibitors [28], TYK2/JAK1 inhibitor [29], Rho-Associated Kinase (ROCK2) inhibitor [30], Sphingosine-1-Phosphate (S1P) agonist [31] and aryl hydrocarbon receptor (AhR) agonists [32]. All current therapies display adverse effects, such as nasopharyngitis, upper respiratory tract infections, fatigue, headache and even tuberculosis, therefore adjuvant therapies that can aid the standard ones are searched.

Immunoglobulin Y (IgY) has important characteristics like high tolerability, being essentially a component of the human diet. Hence, it can be used even in subjects that are allergic to egg components because the purified IgY does not contain allergenic ovalbumin [33]. Since IgY cannot link to the Fc receptors or to the complement system expressed by the mammalian cells, administering IgY does not trigger adverse effects [34,35]. A report published more than 20 years ago has shown in animal models that purified IgY does not trigger an IgE response, therefore no allergic reaction [36]. Moreover, the systemic administration of IgY has shown that this Ig can have anti-viral and/or anti-bacterial potency [37]. IgY can neutralize bacteria and viruses, hindering their replication [38,39] therefore passive immunization can be used in humans because it will rapidly give a positive clinical response. In the last decade, IgY has gained an increased scientific attention due to its specific characteristic and biological potency [40].

In Ps, association of bacterial strains residing in the digestive tract of patients was reported, staring from the incidence of *H. pylori* [41], of *Candida albicans* [42] and ending with the major gut dysbiosis registered in these patients, dysbiosis that can influence the skin microbiota favoring thus flare-up of the psoriatic events [43].

Our previously published work has shown that in psoriatic dermatitis murine models, although involving just a psoriatic-like skin lesion, significant alterations of lymphocytes percentages and important changes in NK cell phenotype, in both peripheral blood and spleen were found [43,44]. Considering all the accumulated data, we have initiated in the current study a Ps experimental model in which an adjuvant therapy using oral IgY developed against several pathogenic bacteria to evaluate the potency to alleviate the psoriatic lesions and to restore the immune-related mechanisms. Imiquimod murine model (IMQ-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine) was used to develop the experimental psoriatic dermatitis and further evaluate if the orally given IgY treatment would clinically improve the experimental Ps and would restore the cellular immune parameters.

## **2. Materials and Methods**

#### *2.1. Immunoglobulin Y*

IgY was isolated from the yolk of hyperimmune eggs laid by chickens immunized with human pathogenic bacteria that are antibiotic-resistant, namely groups of pathogens with a high rate of antibiotic resistance responsible for the majority of nosocomial infections. IgY was obtained according to the methodology described in the patent [45]. The obtained IgY is an original product of the ROMVAC Company and is part of the IMUNOINSTANT

brand having a European trademark (EUIPO). IgY that was used is a mix of antibodies raised against the following antibiotic-resistant strains Salmonella spp (enteritidis, typhimurium), Streptococcus pneumoniae, Clostridium difficile, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli [46].
