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Immune System Update in dermatology - Dr. Oki Suwarsa, dr. M.Kes., Sp.KK(K), FINSDV., FAADV.pdf
1. Immune System Update
in Dermatology
Dr. dr. Oki Suwarsa, SpKK(K), MKes
Department of Dermatology and Venereology, Faculty of Medicine,
Hasan Sadikin General Hospital, Universitas Padjadjaran,
Bandung,Indonesia
2. Introduction
• The skin is the largest organ of human body, and its
principal physical function is that of barrier.
• Immunocompetent cells of the skin may also be
divided in cells of the innate skin immune system as
well as cells of the adaptive skin immune system,
each containing recirculating, recruitable, and
resident subpopulation.
4. • Cells of the innate immune system, including
macrophages and dendritic cells (DCs), use pattern
recognition receptors encoded directly by the
germ line DNA, respond to biochemical structures
commonly shared by a variety of different
pathogens, and elicit a rapid response against
these pathogens, although no lasting immunity is
generated.
5. • In contrast, cells of the adaptive immune systems, T
and B lymphocytes, bear specific antigen receptors
encoded by rearranged genes, and in comparison
to the innate response, adaptive immunity develops
more slowly
• A unique feature of the adaptive immune response
is its ability to generate and retain memory; thus, it
has the capability of providing a more rapid
response in the event of subsequent immunologic
challenge.
6. • Although the innate and adaptive immune
responses are distinct, they interact and can each
influence the magnitude and type of their
counterpart.
7. Acne: A New Model of Immune-mediated
Chronic Inflammatory Skin Disease
Acne is a chronic inflammatory disease of the
sebaceous-pilosebaceous unit
Non-inflammatory acneic lesions comedones
Histopathological
examination
Immuohistochemical
analysis
Inflammation
8. • Acne primarily affects the pilosebaceous follicles (PSF)
1. The presence of androgen receptors on the PSF cells
(i.e. keratinocytes and sebocytes)
2. The specific activity of the 5α-reductase on such cells;
3. Gain of function genetic polymorphisms of such
receptors in patients with acne
Acne: A New Model of Immune-mediated
Chronic Inflammatory Skin Disease
9. Gollnick HP. From new findings in acne pathogenesis to new approaches in treatment.
Journal of the European Academy of Dermatology and Venereology. 2015 Jun 1;29(S5):1-7.
12. Genetic Factors
TLR 2
TLR 4
Pathogen
recognition
receptors
• Recognition of
P. acnes
• Regulate
downstream
innate immune
events
• A allele of the Arg753Gln polymorphism of TLR2 gene is
missing and that the Asp299Gly and Thr399Ile changes
of TLR4 occur simultaneously
MUC1
(cell surface mucin)
Mucins
involved in various
processes during
pathogen infection
13. • Genetic polymorphisms in Japanese patients with
severe acne would increase MUC1 pathogen-
binding ability enhancing bacterial colonization
and susceptibility.
• Some reports of the role of TNFA promoter SNPs in
the pathogenesis of acne vulgaris
• The TNFA -308G>A polymorphism was common
⬆⬆⬆ release of TNF-α by both keratinocytes and
sebocytes in carriers of the TNF-α-308 SNP
Genetic Factors
14. • Genetic modifications to IL-1 pathway can be
relevant for the pathogenesis of acne
• Patients carrying this SNP result in enhanced
cleavage of pre-IL-1α, with an increased
production of the mature isoform
• Recent case-control study from Saudi Arabia
significant association of IL- 4R (Q551R A/G) genetic
polymorphisms susceptibility of acne vulgaris
rather than severity
Genetic Factors
15. P. acnes as a trigger for the
development of acne lesions
• Triggering factors follicular colonization by P. acnes
Gram + anaerobic Aerotollerant
Normal resident
microbiota of the
skin, oral cavity,
genitourinary tractcs
16. P. acnes as a trigger for the
development of acne lesions
The most
dominant bacteria
Moist site:
Corynebacteria
Staphylococci
β-Proteobacteria
Sebaceous site:
• Propionibacteria
• Staphylococci (in
particular
Staphylococcus
epidermidis)
Dry site:
Mixed population of
bacteria
17. • “Dysbiosis” imbalance of microorganisms
• Acneic skin bacterial communities is imbalanced
⬆⬆⬆ P. acnes and ⬇⬇⬇ S. epidermidis
• Antimicrobial peptides (PAMs) such as
batteriecidine, epidermine, epilancine k7, phenol
soluble moduline γ and δ ⬇⬇⬇
• PAMs inhibit P. acnes proliferation
P. acnes as a trigger for the
development of acne lesions
18. • P. acnes displays several activities that are able to
promote the development of acne skin lesions,
including the following:
1. to promote follicular hyperkeratinisation;
2. to induce sebogenesis;
3. to trigger an infammatory response by the activa-
tion of innate immunity, that is followed by a
P. acnes-specific adaptive immune response
P. acnes as a trigger for the
development of acne lesions
19.
20. Free fatty acids and β-
defensins (hβD2)
Metabolize triglycerides
Lipases
P. acnes
P. acnes triggers the release of
proinflammatory factors
21. Induce follicular
hyperkeratinization
Adherence
P. acnes ⬆⬆
Chemoattractant
neutrophils
Free fatty acids
β-defensins
(hβD2)
protective role against
P. acnes colonization
chemoattractive for
immature dendritic cells and
memory T cells
P. acnes triggers the release of
proinflammatory factors
22. • P. acnes-derived proteases release hβD2, LL37, as
well as several metalloproteases (MMP1, 2, 3, 9, 13)
• P. acnes synthesizes coproporfirin III production:
IL-8
reactive oxygen species (ROS)
catalytic agents that induce the peroxidation of
sebum- derived squalene
P. acnes triggers the release of
proinflammatory factors
23. • Production of superoxid anions + ⬇ keratinocyte
synthesis of antioxidants such as glutatione and
vitamin E PSF hyperkeratinization and the
development of a microaerophilic environment
• P. acnes proliferation proinflammatory cytokines
by keratinocytes, and PPARα and γ stimulation
followed by 5-lipoxydase and B3-leukotriene
• Finally, PPAR γ receptors trigger sebocytes to
produce COX2 and PGE2
P. acnes triggers the release of
proinflammatory factors
24. P. acnes activates innate
immunity
• P. acnes activate the complement cascade by both
the classic and the alternative pathways perifollicular
area ⬆⬆ accumulation C5a
• P. acnes stimulates TLR2 and 4 hyperexpressed on
follicular keratinocytes
• TLR2 and 4 stimulation by P. acnes ⬆⬆ IL-1α, IL-1β, TNF-α
and GM-CSF chemotactic neutrophils, lymphocytes
macrophages
• P. acnes stimulates CD36, a scavenger receptor
expressed on keratinocytes and sebocytes ⬆⬆
superoxide anions that form peroxynitrites from the
combination with nitric oxide
25. P. acnes activates innate
immunity
• CD36 ⬆ release of free fatty saturated acids in
sebocytes, ⬆⬆⬆ hypre- production of hβD2
• These results confirm a prominent role for innate
immunity that, via the production of antimicrobial
peptides, inflammatory cytokines and MMPs, is able
to trigger the inflammatory response
26. • Activation of innate immunity development of an
adaptive immune response against P. acnes
• The most important step maturation of dendritic
cells
• P. acnes stimulate both keratinocytes and
sebocytes Nk T cells produce ⬆ IL-15 and GM-CSF
induce dendritic cell maturation.
P. acnes stimulates a specific
adaptive immune response
27. • Mature dendritic cells express CD1b expose P. acnes
antigens on class I and II MhC activation of B and T
cells in the draining lymphnode antibody production
• P. acnes antigens that are recognized by dendritic cells
are:
peptoglicans,
lipoteicoic acid,
lipo-arabinomannans, lipoglicans (DNAk)
different types of heat shock proteins, including
GroEL, which has a high homology with human heat
shock protein 60
P. acnes stimulates a specific
adaptive immune response
28. • The B-cell P. acnes results in the production of
IgG and IgM,
• P. acnes mixed Th17/Th1 IL-17A and IFN-γ
from specific CD4+ T cells in vitro.
P. acnes stimulates a specific
adaptive immune response
29. Suh DH, Kwon HH. What's new in the physiopathology of acne?. British Journal of
Dermatology. 2015 Jul 1;172(S1):13-9.
30. • Androgens interact with the specific androgenic
receptors on sebocytes leading to the
production of IL-6, TNFα and hβD2,
• Chemotactic and activating effect on monocytes,
immature dendritic cells and T cells
• Sebocytes and follicular keratinocytes release
CRh, CRh-binding protein, CRh receptors 1 and 2
(CRhR1 and 2), as well as some melanocortins, such
as ACTh, MSh and its receptor MCR5
P. acnes stimulates a specific
adaptive immune response
31. • All these data suggest that PSF can be
considered as a neuroendocrin organ
• The activation of this neuroendocrin pathway is also
able to explain stress-induced exacerbation of
acne
P. acnes stimulates a specific
adaptive immune response
32.
33.
34.
35. • Acne is a chronic inflammatory disease of the
sebaceous-pilosebaceous unit.
• In acneic skin, the relationship between bacterial
communities granted by microbial interdipendence
is imbalanced (dysbiosis), with consequent
overgrowth of P. acnes and signicant reduction, up
to disappearance, of Staphylococci species.
• Release of proinflammatory factors and the
following activation of both innate and adaptive
immunity lead to follicular hyperkeratinization,
sebogenesis and inflammatory response
CONCLUSIONS
36. REFERENCE
• Suh DH, Kwon HH. What's new in the physiopathology of acne?. British Journal
of Dermatology. 2015 Jul 1;172(S1):13-9.
• Selway JL, Kurczab T, Kealey T, Langlands K. Toll-like receptor 2 activation and
comedogenesis: implications for the pathogenesis of acne. BMC
dermatology. 2013 Sep 6;13(1):10.
• Gollnick HP. From new findings in acne pathogenesis to new approaches in
treatment. Journal of the European Academy of Dermatology and
Venereology. 2015 Jun 1;29(S5):1-7.
• Maulinda S, Hindritiani R, Ruchiatan K, Suwarsa O. Comparison of Interleukin-
17 Serum Level between Papulopustular and Comedonal Types of Acne
Vulgaris. Majalah Kedokteran Bandung. 2016 Sep 30;48(3):160-3.
• Modlin RL, Miller LS, Bangert C, Stingl G. Innate and Adaptive Immunity in the
Skin. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K, editor.
Fitzpatrick’s dermatology in general medicine. 8th edition. New York: McGraw-
Hill; 2012. p. 105-24.
• Bos JD. Skin Immune System. In: Bos JD, editor. Skin Immune System Cutaneous
Immunology and Clinical Immunodermatology. 3th edition. New York: CRC
Press; 2011. p. 3-11.