6th.

Second

Regional Immunity

Rakan Fayez El-Hamad

Maram Zeidan

‫الرا أبو سلمى‬

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 Regional Immunity
Although the same basic principles underlie immune functions all over the body, the
immune system still displays various characteristics in different body regions according
to their specific buildup and function. Such body regions include:

1) Those whose physiological roles (their functions) require direct interaction with the
outside environment, so they are covered by epithelial barrier tissues and are in direct
interaction with their respective normal flora systems.
They are two types:
→ Mucosal Immune System: specialized IS in body systems lined with mucosa, mainly
immunity in the Gastrointestinal tract, and other mucosal tissues like Genitourinary
tract and Respiratory tract.
→Cutaneous Immune System: IS interacting with the skin, thus protects it.
2) Those areas which are particularly susceptible to inadvertent injury by inflammatory
and immune responses, and therefore experience immune privilege.‫االستجابة المناعية فيها قليلة‬
These regions are: Brain, eyes, testis and fetus of the pregnant woman.
Immunity in areas with direct exposure to the environment:
The basic organization of those immune systems is:
1. Integration of innate and adaptive immune mechanisms (incorporate & work
together to achieve the strongest possible IR).
2. Outer epithelial layers to prevent microbial invasion (prevent microbial entry to
the body).
3. 3.Underlying connective tissues (e.g. lamina propria in mucosal areas, dermis in
skin) which contain scattered immune cells of various types (e.g. lymphocytes,
dendritic cells, macrophages), some of which may be peculiar to that specific
region.
→In mucosal areas, these immune cells might take also the form of local specified
arrangements called mucosa-associated lymphoid tissues (i.e. MALTs).
(MALTs‫)ممكن تتجمع الخاليا المناعية مع بعض وتشكل ال‬
4. Draining local lymph nodes (lymph drained from those areas goes to local LN
where the IR might take place.
5. Preferential homing of lymphocytes to the specific region in which they were
initially activated.
‫يعني بترجع الخاليا للمكان إلي طلعت منّه حتى توفر أكبر قدر ممكن من الحماية المستقبلية للجسم في حال تعرضه لنفس‬
Antegens‫ال‬

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 6. Importance of regulation to prevent unnecessary responses to nonharmful
substances. ‫ فبتتعرض لكتير مواد أغلبها‬,‫يعني هاي المناطق من الجسم على اتصال مباشرو دائم مع البيئة الخارجية‬
.‫ فبنحتاج إنه هاي األجزاء تميزها وما تعمل استجابة ضدها‬,‫غير ضارة وممكن حتى تكون ضرورية للجسم‬
Let’s talk specifically about the main features of Mucosal Immune System:
1) Relatively impermeable epithelial barriers.
2)Secretion of mucin and defensins.
3) Localized subepithelial collections of lymphoid tissue (i.e. MALTs).
4) Constant sampling of antigens beyond the barrier by immune cells from within.
5) Integration of proinflammatory and regulatory signals generated by microbial
products binding to immune receptors on epithelial and dendritic cells
(to differentiate between harmful & harmless objects).
6) Reliance on secretory IgA-mediated humoral responses.
7) Stimulation of particular types of effector and regulatory T cell responses.
Immunity in the Gastrointestinal Tract:
The gastrointestinal tract (GIT) is characterized by its large surface area and
abundance of normal flora, which creates challenges in identifying potentially harmful
microbes and telling them apart from the much more numerous normal flora microbes.
Both the innate and adaptive immune responses play an important part towards
achieving that goal.
Various GI epithelial cell types play
different roles related to immunity:
1) Goblet cells: located at the top
of the intestinal villi and secrete
mucus.
2) Paneth cells: located at the
bottom of the crypts and secrete
antibacterial peptides.
3) Microfold (M) cells: found in the
dome structures overlying
lymphoid tissues and act in antigen
sampling.
→ 1&2 play roles in innate immunity, while 3 play a role in adaptive immunity.
→ Ag sampling is taking the Ag from the lumen to the underling tissue, specifically to
the immune cells, to determine whether it’s harmful or not.

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Innate immunity in the GIT:
1) Mucins: they are secreted and cell surface glycoproteins produced by mucosal
goblet cells and submucosal glands, the composition and rate of production of mucin is
affected by various stimuli (e.g. cytokines, TNF, neutrophil products).
These mucins would then form:
→ Secreted mucus: a single layer in the small intestine, and two layers in the colon,
with the bacteria trapped away from the epithelial surface
(epithelial surface ‫)يحد من تماس البكتيريا مع ال‬
→ Glycocalyx(membrane bound/cell surface mucin): which is formed by the
combination of membrane-bound mucins with various glycolipids, they would provide a
barrier against microbes by their decoy function

mucus ‫ وبترتبط مع ال‬molecules from the epithelial surface ‫إلي بصير إنه بتفك‬
lumen ‫ الموجود بال‬Ag ‫إلي معه على ال‬molecules ‫ بربط ال‬mucus ‫ بعدين ال‬,,
.‫يوصله‬
Mucins would ‫ إنه‬a‫منعه‬
provide ‫بكون‬against
barrier ‫هو فعليّا‬microbes
‫ و‬epithelial surface
, decoy ‫وصل لل‬
function, ‫بوهمه إنه‬
and matrix for ‫وبهيك‬
display of antimicrobial peptides.

2) Antibacterial peptides: produced by the intestinal epithelium cells, affect the integrity
of microbial structure.
→Defensins: disrupt the integrity of microbial outer membranes (in Gram –ve bacteria)
-defensins: (e.g. HD5, HD6): produced by the small intestinal Paneth cells as well as
by neutrophils.
-defensins: produced by colonic crypt cells.
→C-type lectins (e.g. REGIII ): bactericidal substances which bind to peptidoglycan
(in Gram +ve bacteria).
3) Pattern recognition receptors
→ Membrane-bound: Toll-like receptors (TLRs)
→ Cytoplasmic: nucleotide oilgomerization domain (NOD)-like receptors (NLRs)

They recognize pathogen-associated molecular patterns (PAMPs)

(e.g. lipopolysaccharide, peptidoglycans), thus promoting responses against
pathogens whilst suppressing those against commensals.
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TLR and NLR activation might lead to:
1. Tightening of interepithelial junctions (Increase integrity, decrease permeability)
2. Promoting intestinal motility and epithelial proliferation (Increase integrity)
3. Stimulating the secretion of antimicrobial peptides and IgA.
Compartmentalization may help in guiding the nature of the immune response upon
TLR activation.
Ag ‫ ال‬,‫ مثالا هاي الصورة‬.‫ بمكان معين‬TLRs‫قدرة الجسم على التعرف على خطورة جسم معيّن عن طريق حصر ال‬
‫ بس بالسيتوبالزم بتواجهه‬,pattern recognition molecule ‫ للخلية ألنه مافي على السطح‬invasion ‫بلّش يعمل‬
‫ وبمنعوه من إنه يكمل طريقه ويسبب مرض فبنفهم إنه‬TLR ‫ بتواجهه ال‬Basement membrane ‫ وعلى ال‬NLR‫ال‬
.‫ بأماكن معينة‬expression ‫ بصيرلها‬PRMs‫ال‬

Localized Expression of
Pattern Recognition
Molecules

4) Innate lymphoid cells (ILCs): derived from the lymphoid lineage but lack specific
antigen receptors. They are activated by cytokines (some of which are called
alarmins), after which they exhibit helper functions analogous to TH subsets.
ILC types include:
→ ILC2s: activated by IL-25 + IL-33 to secrete IL-5 (which activates eosinophils) and
IL-13 (which increases mucus production). Both those functions help in fighting off
parasitic infestations. Exhibit TH2
→ ILC3s: activated by the alarmin IL-1b + IL-23 to produce IL-17 + IL-22, thus
promoting inflammation, defensin production, and tight junction function. Exhibit TH17

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Adaptive Immunity in the GIT:
The major features of adaptive immunity in the GIT are:
1) Relative importance of humoral immunity in the form of secretory IgA.
2) Cell-mediated immune responses are primarily mediated by TH17 cells.
3) Importance of Treg cells in controlling immune responses towards tolerance of
antigens from food and commensal microbes.
normal flora‫يعني التّحكم بالجسم إنه ما يعمل استجابة مناعية ضد األكل و ال‬

→Gut-associated lymphoid tissue (GALT) takes the form of such structures as:
- Peyer’s patches(at the beginning of the digestive tract in the intestine)
- Tonsils (whether lingual, palatine or nasopharyngeal)
- As well as smaller aggregates of lymphoid follicles
Those follicles are primarily made of B cells, TH cells, follicular dendritic cells and
macrophages. The dome areas lie between the follicles and the overlying epithelium,
richer in B cells, while parafollicular areas are particularly richer in T cells compared to
other GALT areas.
→ M- Cells: M cells move particulate matter from the lumen first by endocytosis, then
by moving the endosomes across the cytoplasm to the basolateral membrane.
There, they would be delivered through exocytosis to B cells and dendritic cells
whether within GALT or scattered in the lamina propria.
- Unlike macrophages or dendritic cells, M cells do not process the matter which it
transports and can’t present them to T cells. The antigens delivered to the lamina
propria would then initiate immune responses whether locally or in draining lymph
nodes.
- During TH cell activation, dendritic cells secrete retinoic acid to imprint a gut-homing
phenotype on B cells and effector T cells through integrin- and chemokine receptor-
dependent mechanisms.

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Humoral immunity in the GIT:
→ Secretory IgA (whether produced locally or, in the case of breastfeeding, secreted in
colostrum or breast milk) is the main antibody isotype in the GIT, and it mainly acts
through neutralization( direct binding with the Ag and stop it’s pathogenicity) or
reducing microbial motility( i.e by binding to bacterial flagella).
→ Chemicals which mediate IgA isotype switching include the cytokines TGFb and
APRIL, retinoic acid, and nitric oxide.
→ IgA-producing plasma cells in the lamina propria secrete IgA in the form of a dimer
of 4-chain basic units where a J chain is bound to the Fc regions of the chains.
The dimer would then bind to the poly-Ig receptor, move across the cytosol through
transcytosis, then released from the apical membrane through cleavage of the poly-Ig
receptor (on the basal area of the epithelium, can transport both IgA and IgM that’s
why it’s called poly), thus giving rise to the secretory component).

Other Aspects of Adaptive Immunity ( T cells):

Most of the intraepithelial T cells are CD8+ with a
significant T cell population, while elsewhere in the gut
the CD4+ T cells predominate. As antigen-presenting cells,
dendritic cells and macrophages sample antigens which
have breached the epithelial barrier, and sometimes even
send projections across the epithelium to take samples
from the lumen.
The TH17 pattern predominates in the gut, with less
occurrence of the TH2 and TH1. Treg cells are also
relatively abundant in the gut, as their formation is usually
induced by TGF and retinoic acid, and they usually exert
their action through producing IL-10.
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Immunity in Other Mucosal Areas:
Immunity in the respiratory tract→ it shares many features with that of the GIT.
It produces mucus and defensins + cathelicidins (which have antimicrobial properties)
It also produces surfactant proteins (which are involved in viral neutralization, microbial
clearance and inflammatory suppression)
Note: The mucociliary escalator is an active mechanism to keep the tract free from any
foreign debris ‫زي درج متحرك بنضف مجرى التنفس بإنه يطلع الشوائب لبرا أو يدخلها للجهاز الهضمي حتى يتم التخلّص منها‬
Immunity in the genitourinary tract→ shows less prominence of MALTs compared
to other mucosal areas(mostly scattered), and it is peculiar in the fact that most of the
antibodies in genital secretions are of the IgG isotype
(Remember: In the GIT IgA predominates)
The other IS that is exposed to the environment is:
Cutaneous Immune System
(Innate)→ Besides providing a physical barrier function, the epidermal keratinocytes
produce antimicrobial peptides (e.g. defensins, cathelicidins) and various cytokines.
→ If this barrier is breached, dermal macrophages, mast cells and ILCs (Innate
lymphoid cells) initiate innate immune responses.
i.e: ILCs 1, which exhibit TH1 cells, and they are activated by IL-18 and produce IFN
→ PAMPs and damage-associated molecular patterns (DAMPs) activate pattern
recognition receptors (e.g. TLRs)
(Adaptive)→ Antigen processing and presentation
in the skin is carried out by the epidermal
Langerhans cells and the dermal langerin-
expressing dendritic cells
These APC interact with the cutaneous T cell
population, 95% of which have a memory
phenotype (98% of which reside in the dermis and
only 2% in the epidermis)
→ Upon T cell activation, vitamin D appears to
play a major role in imprinting homing pattern on
them. (Remember: In GIT mucosa retinoic acid
plays this role).

Cutaneous Immune System

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Immune-Privileged Areas
Areas that are overly sensitive to the adverse effects of immune reactions, therefore the
immune response is tweaked away towards a more suppressed one. These areas include:
1) Brain. 2) Eyes. 3) Testis. 4) Fetus of the pregnant mother
.)‫ فاالستجابة فيها بتكون مضعفة (مش معدومة‬,‫معرضة جداا توصل لألعراض الجانبية لالستجابة المناعية‬
ّ ‫الفكرة بهاي األماكن إنها‬
• Mechanisms which suppress immune and inflammatory responses in the Brain:
1. The tight junctions among the local microvascular endothelium (i.e. blood-brain barrier)
2. The action of neuropeptides
3. Scarcity of dendritic cells (relatively low amount of them)
4. The relatively high threshold for microglial activation
→ Even though, a basic level of immune response still takes place there.
The evidence: The occurrence of opportunistic infections in the brain and the presence of local
lymphatics.
• Features which contribute to immune privilege of the Eye:
1. Corneal avascularity
2. The blood-eye barrier near the anterior chamber (bacause of the tight junctions)
3. Absence of lymphatics there
4. Presence of soluble factors with immunosuppressive and antiinflammatory
properties in the aqueous humor
• Features which contribute to immune privilege of the testis:
1. A blood-tissue barrier which limits cellular access into testicular tissue
2. The antiinflammatory effects of androgens (i.e Testosterone)
3. immunosuppressive effects of TGF

• Fetus of the Pregnant Mother: the fetus represents a naturally-occurring allograft, so

various mechanisms are needed to prevent the maternal IS from attacking it and
terminating the pregnancy. These mechanisms are:
1. Trophoblastic expression of HLA-G : a nonpolymorphic class I MHC molecule which
inhibits NK cell function and don’t express cytotoxic t cells
2. Lack of costimular molecules in the trophoblast cells
3. functional inhibition of immune responses in the decidua(part of placenta)
4. Treg cells’ role in maternal tolerance of the fetus.

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