IMMUNITY OF FEMALE GENITAL TRACT

Kanadi Sumaprajakanadi_sumapraja@fk.ui.ac.id

Departemen Obstetri dan GinekologiFKUI-RSCM, Jakarta

IMMUNE RESPONSE

Property Innate immune system Adaptive immune systemReceptors Fixed in genome, rearrangement is not

necessaryEncoded in gene segment, rearrangement necessary

Distribution Non-clonal, all cells of a class identical All cells of a class distinctRecognition Conserved molecular patterns Details of molecular structureSelf-Non self discrimination

Perfect, selected over evolutionary time Imperfect, selected in individual somatic cells

Action time Immediate activation of effectors Delayed activation of effectors

Vagina-ectocervix: highly vascularized submucosa, non-keratinized stratified squamous epithelium

Innate Immunity: Epithelial cells

Endocervix: Simple stratified columnar epithelium

Endometrium (in the non-pregnant state) or Decidua (during pregnancy)

Endosalpinx: highly vascular mucosa, consisting of ciliated and secretory cells

Four proposed mechanisms for mucus protection; rate and quantity of mucus release, viscous blanket (physical barrier), competitive binding sites, and link to the intestinal immune system.

Mucus Protection

Innate immunity: Bacterial flora

The dominant species in the vagina of healthy pre-menopausal women was initially identified as Lactobacillus acidophilus - L. crispatus, L. gasseri and L. jensenii.

Atopobium, Megasphaera and Leptotrichia – another lactic-acid producing species - also capable of producing metabolites with an unpleasant smell.

Lactic acid production is crucial to the maintenance of a healthy vaginal ecosystem - acidic pH prevents the overgrowth of potentially pathogenic microorganisms. Additional benefits for the host of lactobacillus predominance are production of hydrogen peroxide and bacteriocins

Innate immunity: Fluctuation in vaginal flora

The composition of the vaginal ecosystem is not static but changes over time and in response to endogenous and exogenous influences

Variables include: stage of the menstrual cyclepregnancyuse of contraceptive agentsfrequency of sexual intercoursespecific sexual partnersvaginal douchinguse of panty liners or vaginal deodorantsutilization of antibiotics or other medications with

immune or endocrine activities

Innate Immunity

Detection of pathogen invariant molecular structuresSynthesis of antimicrobial moleculesCytokine and chemokine expression which provide early signals to themucosal immune system

Innate immunity: Toll-like receptors (epithelial cells)

Recognition of a PAMP (Pathogen Associated Molecular Pattern) by an innate immune system component triggers a sequence of events leading to the release of pro-inflammatory cytokines and activation of the acquired immune system

The “two-step model” for host response induction by attaching bacteria.Step 1: Bacterial attachment to epithelial cell receptors triggers cell activation through specific transmembrane signaling pathways. In the absence of this first signal, there is no response, and if the bacteria persist, an asymptomatic carrier state is established.

Step 2: Epithelial cells are activated, chemokines are secreted, and inflammatory cells are recruited into the tissues. Subsequently, they cross the mucosal barrier, and in the process infection is cleared. Defective inflammation leads to tissue damage and scarring, owing to poor bacterial clearance and tissue destruction by cells trapped in the tissues.

(Modified from Svanborg et al. The “innate” host response protects and damages the infected urinary tract. Ann. Med. 2001, 33:563–570.)

Innate immunity: Defensins (epithelial cells)

Positively charged peptides that rapidly bind to the negatively charged surface of bacteria. The interaction results in the disruption of the bacterial membrane and cell lysis.

This protein recognizes mannose, N-acetylglucosamine and fucose carbohydrate moieties present on microbial surfaces. Binding induces activation of the complement system and deposition of complement components on the microbialmembrane. This leads to the direct lysis of sensitive bacteria or to microbial opsonization by phagocytic cells

Innate immunity: Complements

Components of the mucosal immune system

ADAPTIVE IMMUNITY

The number of leukocytes (within the CD45 gate) as a percent of the total number of dispersed cells. All data represented are from 13–26 samples; proliferative, 5–7; secretory, 5–11; and inactive, 2–7. *For all stages grouped together, fallopian tube (FT) was significantly different from ectocervix (ECX) and from vaginal mucosa (VM). For proliferative stage, FT was significantly different from ECX and from VM.Inactive stage uterus (UT) differed from proliferative UT and from secretory UT. Inactive cervix (CX) differed from secretory CX.

Cellular immunity

T Cells (CD3), neutrophils (Cd66b), B cells (CD19), and monocytes (CD14) in tissues of the reproductive tract at different stages of the menstrual cycle.

Cellular immunity

Adaptive immunity at mucosal surface – sIgA and sIgMThe main function of secretory antibodies: in cooperation with innate defense – to perform immune exclusion – keeping microorganisms, bacterial toxins, and other potential harmful antigenic material out of the interior of the body, neutralize such agents, bring penetrating antigens back to the lumen

Humoral immunity

Humoral immunity

IgA J-Chain SC

++ ++ ++ Fallopian tube

- - - Ovary

- - - Myometrium

- - - Endometrium

++ ++ ++ Endocervix

++ ++ + Ectocervix

++ ++ + vagina

Humoral immunity: functions of antibody

Luminal antigens are transported to the Follicle Associated Epithelium (FAE). Dendritic cells process and present antigens to T cells in these lymphoid tissues. CD4+ T cells that are stimulated by dendritic cells then preferentially induce IgA-committed B-cell development in the germinal centre of the lymphoid follicle. After IgA class switching and affinity maturation, B cells rapidly migrate from FAE to the regional lymph nodes through the efferent lymphatics. Finally, antigen-specific CD4+ T cells and IgA+ B cells migrate to effector sites through the thoracic duct and blood circulation. IgA+ B cells and plasmablasts then differentiate into IgA-producing plasma cells in the presence of cytokines (IL-5 and IL-6) that are produced by TH2 cells, and they subsequently produce dimeric (or polymeric) forms of IgA. These dimeric forms of IgA then become secretory IgA by binding to polymeric Ig receptors (which become the secretory component in the process of secretory IgA formation) that are displayed on the monolayer of epithelial cells lining the mucosa. Secretory IgA is then released into the nasal passage and intestinal tract. TCR, T-cell receptor

Adaptive immunity

Trancytosis of polymeric IgA through the epithelium using an active poly-Ig receptor-mediated pathway. The plasma cell synthesizes IgA and J chain, which are joined together and secreted. The polymeric complex can bind via the J chain to the poly-Ig receptor expressed at the basolateralmembraneof the epithelial cell. The complex is endocytosed and transported through theEC to the apical side, where it is cleaved and excreted as sIgA with bound secretory component (SC), a marker of this active transport pathway.

Adaptive immunity

Depiction of the human mucosal immune system. Inductive sites for mucosal immunity are constituted by regional MALT with their B-cell follicles and M-cell (M)-containing follicle-associated epithelium through which exogenous antigens are transported actively to reach APCs, including DCs, macrophages, B cells, and FDCs. In addition, quiescent intra- or subepithelial DCs may capture antigens at the effector site (exemplified by nasal mucosa in the middle) and migrate via draining lymphatics to local / regional lymph nodes where they become active APCs, which stimulate T cells for productive or downregulatory (suppressive) immune responses. Naive B and T cells enter MALT (and lymph nodes) via HEVs. After being primed to become memory / effector B and T cells, they migrate from MALT and lymph nodes to peripheral blood for subsequent extravasation at mucosal effector sites.

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Adaptive Immunity

Thank you