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First lecture: Immune system structure and function. Immune system Immune system like any other system in the body includes: Organs, tissues, cells, molecules and some times fluids. The tissue of the immune system are called lymphoid tissue.

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slide1

First lecture:

Immune system

structure and function

slide2

Immune system

Immune system like any other system in the body includes:

Organs, tissues, cells, molecules and some times fluids.

The tissue of the immune system are called lymphoid tissue.

The cells of the immune system are all blood cells except the RBCs.

The molecules of the immune system are: antibodies. complement, cytokine, chemokines etc.

The fluid of immune system is called lymph.

The lymph: is plasma components.

slide3

OVERVIEW OF THE IMMUNE SYSTEMOrganized similarly to nervous system: Cells of the immune system (IS) found throughout the body, but also found in specialized organs.Cells:lymphocytes, macrophages & monocytes, dendritic cells,granulocytes. All arise from pluripotent hematopoietic progenitor cells in bone marrow.Organs:lymph nodes (found in various locations), thymus, spleen - these constitute the lymphoid organs.

slide6

(not truly a lymphoid

organ, but the source

of IS progenitor cells)

LOCATION

OF MAJOR

LYMPHOID ORGANS

THROUGHOUT

THE BODY

slide7

Lymphoid tissues:Are the sites where the ; – Generation, – Maturation, – Habitationand – Activation of the immune cells take place.

slide8

Lymphocytes:

Major subtypes are T and B cells, responsible for immunological memory.

T cells mature in thymus; B cells in avian Bursa of Fabricius but mammalian fetal liver & bone marrow.

Cells participate in cell-mediated immunity & regulation responses; B cells synthesize Abs.

NK cells are morphologically similar to T & B cells; are cytotoxic in absence of prior stimulation.

slide9

lymphocyte from blood smear,

Wright-Giemsa stain, 1000x

slide10

LOCATION OF THE

BURSA OF FABRICIUS

T and B cells have specific antigen receptors, which play roles in developing immunological memory and in specificity of the immune response to antigens. Both T and B cells secrete proteins called cytokines, which form the communication system among and between cells and cell types.

slide11

T cellsB cells

Ag receptor TCR related to Ig BCR is membrane-bound Ig

but not Ig

Ag recognition in context of MHC can recognize Ag alone

on APC or accessory cells

Functional Th (helper) and subsets of B cells not

subsets Tc (cytolytic) different in function

Secrete Cytokines Ig (as Ab) and cytokines

Surface CD4 and CD8 Ig (among many others)

markers (among many others)

When Ag- Become (proliferating) Become lymphoblasts, then

activated lymphoblasts become plasma cells

Costimulation Yes No

required?

T versus B Cells

slide12

TWO MAJOR TYPES OF T CELLS

Th1 & Th2

Effectors cells

help B cells make Ab

Class I MHC expression – ubiquitous (every where).

Class II MHC expression - constitutive: restricted to B cells, a proportion of monos / macs & DCs after activation: induced on most cell types.

slide13

mono in blood smear Wright Giemsa, 1000 x

macrophage in tissue, H&E stain, 400x

MONOCYTES AND MACROPHAGES

Monocytes are immature macrophages, circulate in blood & accumulate at sites of inflammation. MQs may differentiate in tissue in absence of antigen (e.g. Kupffer cells in liver) or differentiate in response to Ag. They are Ag-presenting cells (APC) and cooperate with B and T cells in mounting immune responses. Also phagocytose microbes; contain bactericidal mechanisms.

slide14

MONOS AND MQS-CONTINUED

Express a myeloid receptor (CD14) which serves as a recognition molecule for a wide variety of bacterial envelope molecules, such as LPS from Gram -ve organisms and components of Mycobacterial and Gram +ve cell walls. Ligation of this receptor leads to MQs activation.

slide15

Also they’re activated by T cell derived cytokines leading to increased phagocytosis and microbicidal activity (increased activity of degradative enzymes, nitrogen and oxygen free radical production and prostaglandins etc.).

slide16

NOTE:

T cell derived cytokines increase the antigen presenting activity of macrophages which, in turn, are able to present antigen to T cells.

This cycle will continue as a positive feedback loop until the antigen is eliminated.

slide17

LPS-activated DCs

DENDRITIC CELLS

DCs are the APCs for primary (1st time) adaptive immune responses. Also constitute major components of the innate immune system and the bridge to adaptive immunity.

Two sites of origin, plasmacytoidDCs (periphery & spleen) and myeloid DCs (bone marrow). So far no major functional differences noted.

slide18

THE DENDRITIC CELL THAT’S NOT A DENDRITIC CELL

Follicular DCs are found in primary & secondary lymphoid follicles but are not of the same origin as plasmacytoid or myeloid DCs. In fact, their exact origin is unknown, though they may be myeloid. FDCs play a role in controlling B cells responses.

FDCs in the spleen

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GRANULOCYTESPolymorphonuclear leukocytes (PMNs) or Neutrophils: Predominant type of white blood cell, rapidly migrate to sites of infection or inflammation. Phagocytic, they have special enzymatic pathways for enhanced bactericidal action. Also called azurophils, due to blue-stained (azurophilic) granules.

slide20

azurophilic staining of PMNs

PMN

Mono

PMN, note tri-lobed nucleus

Wright-Giemsa, 1000x

Comparison of mono to PMN

slide21

Basophil

mast cells

Degranulating

mast cell

intact

mast cell

BASOPHILS AND MAST CELLHave basophilic granules, which contain mediators, especially of allergic responses. Basophils circulate, mast cells found in tissue.

slide22

Eosinophil

Eosinophil

PMNs

Comparison of PMNs to eosinophil

EOSINOPHILS

Have granules that stain red with eosin. Mediate late phase of allergic

response, active in immune response to parasites & tumors (antibody-

dependent cell-mediate cytotoxicity). Granules contain toxic proteins

of high pH.

eosinophil

slide23

Hematopoietic stem cell

Stromal stem cell

ORGANS OF THE IMMUNE SYSTEM

PRIMARY LYMPHOID ORGANS

Primary lymphoid organs are where lymphocytes arise and mature in the absence of antigenic stimuli. They are the bone marrow and thymus. Bone marrow: Source of all hematopoietic progenitor (stem) cells, site of B cell maturation post-birth in mammals.

slide26

Primary lymphoid tissuesThe sites where the blood cells, generation (haematopoiesis) and maturation take place Haematopoiesis takes place:• In yolk sac (first 5 weeks of fetus’s age)• In fetal liver (5-8 weeks of age)• In the whole bone (after 4 months of fetus’s age)In adult the haematopoiesis takes place in the flat bones only (sternum, scapula, skull, pelvis) – Bone marrow: the site where all blood cells generation and maturation (except T cells maturation) take place.

slide28

مغزاستخوان : سه فونکسیون به عهده دارد :

مرکزتولید اکثررده های سلولی مختلف خونی می باشد . درمغزاستخوان Stem Cell لنفوئید ها را می سازد . ازسلول اخیر سلول های T لمفوئید ، B لمفوئید ، NK Cell یا سلول های کشندۀ طبیعی و K Cell ها مشتق می شوند . سلول میلوئیدی دیگر سلولی است که از Stem cellها مشتق می شود و تمام رده های سلول های خونی ازاین سلول مشتق می شوند ازجمله مگا کاریوسیت ها Megacaryocyte که این ها نیز به نوبۀ خود سلول های خونی نوع پلاکت را می سازند.

مونوسیت ها که سازندۀ ماکروفاژها هستند نیزاز Myeloid cellها منشأ می گیرند.

دندریتیک سل ها( dendritic cell) که ماکروفاژهای تخصص یافته هستند نیزازاین سلول ها منشأ می گیرند و ماست سل ها mast cells نیز ازاين سلول ها مشتق گردیده اند.

slide29

دومین وظیفۀ مغزاستخوان این است که به عنوان مرکزی است برای جذب آنتی ژن به دلیل اینکه دارای مقدارزیادی ماکروفاژمی باشد .

مغزاستخوان محلی است برای تولید وذخیرۀ آنتی بادی بطوری که دربعضی موجودات بیش از50% آنتی بادی ها درمغزاستخوان تولید می شوند که بیشتر ازنوع IgG می باشند لذا مغزاستخوان هم می تواند یک ارگان لنفوئیدی اولیه باشد چون همۀ سلول های خونی از آن جا سرچشمه می گیرند وهم یک ارگان ثانویۀ لنفوئیدی زیرا محلی است برای جذب آنتی ژن و پاسخ برعلیه آن .

مغزاستخوان دارای دو بخش جداگانه است :

الف ) Vascular Compatment

ب ) Hematopoetic Compatment

بخش H.Com… محل تشکیل سلول های خونی و بخش V.Com… محل عروق خونی ، سینوس های خونی و RBCها ونیزمغزاستخوان است.

slide31

PRIMARY LYMPHOID ORGANS: THYMUS

The thymus is the site where lymphoid cells undergo maturation and education into T cells prior to release into the circulation. This process allows T cells to develop the important attribute known as self-tolerance. The thymus is found in the thorax in the anterior mediastinum. It gradually enlarges during childhood but after puberty it undergoes a process of involution resulting in a reduction in the functioning mass of the gland. It continues to function throughout life, however.

The thymus is arranged into an outer cellular cortex and an inner medulla. Immature lymphoid cells enter the cortex, where they proliferate, mature, and move to the medulla, from where mature T lymphocytes enter the circulation.

slide36

هورمون های تیموس :

تیموس هورمون های مختلفی تولید می کند وبعنوان یک غدۀ آندوکرین داخلی تلقی می شود ازجمله تیموزینThymosine که دارای سه تیپ آلفا ، بتا و گاما می شود وهرکدام نیزگروهی فرعی دیگری دارند .

اثر این هورمون القاء ظهورآنزیم T.D.T (Terminal Deoxynucleotidyl Transferase ) وهمچنین ظهورReceptor گلبول قرمز برسطح لنفوسیت های T که اصطلاحاً به آن Cd2 می گویند می باشند.

تیمو پوئی تین Thymopoetin : دو نوع دارد ودرتنظیم پاسخ های ایمنی وافزایش جمعیت لنفوسیت های مهارکننده ( T. Suppressor) دخالت دارد که دربیماری های اتوایمیون Auto Immune ایفای نقش می نماید.

Thymic humoral factor : این هورمون می تواند تمایز لنفوسیت های T را تشدید نماید و صلاحیت لنفوسیت های T را درموش های که تیموس آن ها را برداشته اند اعاده نماید.

Factor Thymic serige : بوسیلۀ سلول های اپی تلیال تیموس تولید می شود و باعث القاء ظهورآنزیم های سطحی لنفوسیت های T می شود.

slide37

تیموس دارای دو بخش است :

بخش قشری یا Cortex : ازتعداد زیادی سلول به نام Thymocyte تشکیل یافته است که منشاء آن ها از Pre Thymocyte بوده که این نیز به نوبه خود از Stem Cell درمغزاستخوان منشأ می گیرد. این سلول ها دائماً درحال تقسیم وتمایز بوده وتعدادی از آن ها ازبین می رود وبخشی از آن ها که لازم است تمایزیافته و وارد مدولا Medulla می شود.

بخش مرکزی یا Medulla : این بخش ازبافت اپی تلیال تیموس تشکیل یافته است ودراین بخش اجسامی قراردارند که بنام اجسام هاسل یا Hassal body نام دارند . درسلول های اپی تلیال این بخش مقداری لنوسیت دیده می شود . بنظرمیرسد که لنفوسیت ها درحال آموزش هستند وسلول هایی که لنفوسیت درآن ها درحال آموزش هستند بنام سلول پرستاریا CellNurse نامیده می شوند .

slide38

اجسام هاسل : بیش از90% لنفوسیت های وارد شده به تیموس ازبین می روند وتشکیل اجسام هاسل را می دهند . درداخل تیموس یک دسته سلول دیگر بنام میلوئید سلول وجود دارد که دارای نقاط تاریک و روشن بوده شبیه سلول های ماهیچه ای می باشند وبنظرمی رسد که Muscular distrophy ( دیستروفی عضلانی ) که درجریان اختلالات تیموس ایجاد می شود به دلیل همین سلول های میلوئیدی است .

رگ های خونی که وارد تیموس می شود درناحیۀ کورتکس دارای اندوتلیال و یک لایۀ ، ممبران بازال Membrane basal یا Basment membrane می باشد که این وضعیت همراه وجود ماکروفاژها مانع از ورود آنتی ژن به داخل تیموس می شود . لذا تیموس یک عضو Thymic blood barrier می باشد ، بدین سبب آموزش لنفوسیت ها درداخل تیموس بدون حضورآنتی ژن های خارجی صورت می گیرد.

slide40

THYMUS young

Cortex - dark

Connective tissue

Lobules

Medulla - light

Hassall’s thymic corpuscle

Packed lymphocytes (thymocytes)

round, red, layered

slide41

PRINCIPAL THYMIC CELLS

EPITHELIO-RETICULAR CELL

NAدVE LYMPHOCYTES (THYMOCYTES)

desmosome

MF

disposing of un-approved thymocyte

slide43

Dendritic cells (DC)

B cells

Myeloid DC (CD11c+, CD11b+, CD8-)

CLP

T cells

Langerhans cells (skin)

(CD11c+, CD11b+, CD8+/-, Langerin)

Dendritic cells

HSC

Lymphoid DC (CD11c+, CD11b-, CD8+)

Monocytes

Plasmacytoid DC (CD11c+, B220+)

CMP

granulocytes

Monocyte-derived DC

(CD11c+/-, CD11b+, CD8-)

inflammation

erythrocytes

Megakaryoctes

slide48

Ag PRESENTATION IN LYMPH NODES

from Itano & Jenkins. Nature Immunology 4, 733 - 739 (2003). Antigen presentation to naive CD4 T cells in the lymph node.

slide50

بعضی این ارگان را معادل بورس درپرندگان می دانند که در روی روده ها قرار دارد وشامل دو قسمت است :

الف ) درناحیۀ Ieujenum قراردارد

ب ) درناحیۀ Illeum و Secum قراردارد.

پلاک های پی یر برروی ایلوئوم درهرساعـت 3600000 لنفوسیت تولید می کند که فقط 200000باقیمانده وبقیۀ آن ازبین می روند درحالیکه پلاک های پی یر واقع در ژژنوم درمراحل زندگی جنینی بوجود آمده وتا پایان عمروجود دارند وکارآن ها جذب وپاسخ به آنتی ژن ها است ودرسرراه لنف قراردارند وبصورت ارگان وندول های لنفاوی ثانويه می باشند که مهمترین آن ها طحال است.

slide52

Cortical nodules

(follicles)

Cortex

Medullary

sinuses

SECONDARY LYMPHOID ORGANS

These are the peripheral lymphoid organs: lymph nodes, spleen, tonsils,

adenoids, and lymphoid tissue associated with other organ systems

(MALT for mucosa, GALT for gut, BALT for bronchus and SALT in skin .

LYMPH NODES: filter lymphatic fluid; sites of Ag presentation & cell traffic

Lymph nodes have a fibrous capsule from which trabeculae extend towards the center, forming a framework for the lymphatic sinuses, blood vessels, and parenchyma (cor-

tex, paracortex, and medulla).

slide53

Sub-capsular

Sinus

LYMPH NODES, CONTINUED

Functions of structural elements of lymph nodes

The lymphatic system is a series of vessels which drain and filter the tissue fluids. Lymph enters the node via afferent lymphatics, passes through the sinuses lined with macrophages and leaves via efferent lymphatic (ultimately all drain into the portal vein). Lymphocytes enter the node primarily from the blood via HEV and leave via efferent lymphatics.

DCs migrating from tissue enter the node into the T cell areas. B cells entering nodes from blood must cross the T rich area in transit to the B cell rich areas thus optimizing T-B cooperation.

The B cell rich areas contain mature, resting B cells organized into structures around follicular dendritic cells (primary follicles).

slide54

Lymph node parenchyma is made up of three components:

* cortex

* paracortex

* medulla

Cortex (B cell area)

B cells enter the lymph node via HEVs and pass to the follicles. If activated by antigenic stimulation, they proliferate and remain in the node. Unstimulated B cells, however, pass out rapidly from the node to return to the general circulation.

slide55

Activated B cells within the lymphoid follicles are known as follicle centre cells. The pale staining central area of a secondary follicle is known as a germinal centre and this is surrounded by a mantle zone consisting of small, naive B cells and a few T cells. The follicle centre cells within the germinal centres consist of cells with cleaved nuclei (centrocytes) and cells with larger more open nuclei and several nucleoli (centroblasts).

slide56

Stimulated mature B cells responding to antigen change into centrocytes and then centroblasts.

The centroblasts leave the follicle and pass to the paracortex and medullary sinuses, where they become immunoblasts.

The immunoblasts divide to give rise to plasma cells or memory B cells which are ready for their next encounter with specific antigen.

B cells alone are not able to mount immune responses.

slide57

They are assisted by accessory cells: * sinus macrophages (highly phagocytic) * tingible body macrophages (ingest cellular debris in germinal centres) * marginal zone macrophages (found beneath the subcapsular sinus) * follicular dendritic cells

slide58

Paracortex (T cell area)The paracortex contains lymphocytes and accessory cells along with supporting cells. It is the predominant site for T cells within the lymph node.The various types of T cell enter the node from the blood via the HEVs. When activated they form lymphoblasts, which divide to produce a clone of T cells responding to a specific antigen.

slide59

Activated T cells then pass into the circulation to reach peripheral sites.Accessory cells: Interdigitating cells are numerous in the paracortex and act as Ag-presenting cells. MedullaThe medulla is comprised of: * large blood vessels * medullary cords * medullary sinuses

slide60

The medullary cords are rich in plasma cells, which produce Ab that pass out of the node via the efferent lymphatic. Macrophages are also numerous within the medulla. Lymph passes into the node through the afferent lymphatic into the marginal sinus, though the cortical sinuses to reach the medullary sinuses before leaving via the efferent lymphatic. Particulate matter in the lymph is removed by macrophages.

slide61

Antigens are taken up by antigen presenting cells and these facilitate the specific immune response. Less than 10% of lymphocytes enter the node in the lymph, the large majority entering from the blood via the HEVs.

slide63

PALS

There are two distinct components of the spleen, the red pulp and the white pulp.

The red pulp consists of large numbers of sinuses and sinusoids filled with blood and is responsible for the filtration function of the spleen.

The white pulp consists of aggregates of lymphoid tissue and is responsible for the immunological function of the spleen.

slide64

The spleen serves two major functions: *It is responsible for the destruction of old red blood cells (RBCs);*It is a major site for mounting the immune response. The spleen behaves similar to a lymph node but instead of filtering lymph, it filters blood. Blood entering the spleen travels through progressively smaller arterioles until it is deposited in the red pulp, where the RBCs are processed.

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The interface between PALS (peri artherial lymphoid sheath) and blood is a region of intense phagocytic activity and sets the stage for immune responses. The immune reactivity of the spleen is especially effective for dealing with blood-borne antigens such as bacteria.

slide66

Red pulp

INSIDE THE SPLEEN

Red pulp

The red pulp has a complex system of blood vessels within it, arranged to facilitate removal of old or damaged RBCs from the circulation.

A small proportion of splenic blood flow passes through more rapidly without undergoing filtration.

slide67

Capsule

Trabecula

Primary

follicle

Vascular

sinusoids

Marginalzone

White pulp

Periarterial

lymphatic

sheath (PALS)

Germinal center

Red pulp

Artery

Vein

INSIDE THE SPLEEN CONTINUED

White pulp

The white pulp contains T cells, B cells and accessory cells. There are many similarities with lymph node structure. The purpose of the white pulp is to mount an immunological response to antigens within the blood. The white pulp is present in the form of a periarteriolar lymphoid sheath. This sheath contains B cell follicles and T cells. At the edge of the T zone is a region known as the marginal zone where larger lymphocytes and antigen presenting dendritic cells are located.

slide68
طحال Spleen :
  • بزرگترین ارگان لنفاوی ثانویه است که سرراه گردش خون وجود دارد ودارای دو قسمت است :
  • 1- پولپ سفید White Pulpe 2- پولپ قرمز Red Pulpe
  • سطح طحال ازبافت همبندی سختی پوشیده شده است که ترابکولاهایی از آن منشعب می شوند وبه داخل طحال وارد می شوند وآن را به لوبول های متعددی تقسیم می کنند . کمربند لنفوسیتی درپولپ سفید قرارگرفته و فولیکول های اولیه در این قسمت هستند . طحال دراین قسمت آنتی ژن را شناسایی کرده وعرضه می نماید (پولچ سفید).
  • درپولپ قرمز سینوس های خونی ، الیاف رتیکولی ، گلبول های قرمز و ماکروفاژها قراردارند . اگرآنتی ژن برای باراول وارد شود توسط ماکروفاژها گرفته می شوند واگربرای باردوم وارد شوند توسط دندریتیک سل ها گرفتارمیشوند . درصورت اخیربرای آنتی ژن ،آنتی بادی موجود است. اگرآنتی ژن غیرمحلول باشد بین الیاف های رتیکولی گیرمی کند ، مثل ابتلا به لیشمانیا یا ناهنجاری های گلبول های قرمز که موجب بزرگی طحال می شود
slide69
طحال دارای دو سیستم گردش خونی است : باز و بسته
  • گردش خونی باز زمانی به کارمی رود که آنتی ژن درسرراه ازطحال عبورکند.
  • طحال بطورکلی دارای فعالیت های زیر است :
  • 1- محل عمدۀ تولید آنتی بادی
  • 2- محل عمده برای شناسایی و عرضۀ آنتی ژن ، تولید پاسخ با همکاری لنفوسیت های B وT وماکروفاژها
  • محلی برای جذب مجدد آهن ناشی ازانهدام RBCها
  • محل انهدام لنفوسیت های پیر و گلبول های قرمزپیر و لکوسیت های پیر
  • احتمالاً هورمون هایی تولید می کند برای زمانی که مغزاستخوان ازکاربیفتد تا نقش خون سازی را به عهده بگیرد
  • جذب قطرات چربی ، بطوری که درافراد دیابتیک که هیپرلیپیدمی داشته باشند قطرات توسط ماکروفاژها برداشته شده وماکروفاژهای طحالی در اینگونه موارد حاوی قطرات چربی هستند.
  • آپاندیس بعنوان ارگان لنفاوی ثانویه وعقدۀ لنفاوی گوارشی است ومحل تجمع گرانولوسیت ها و لنفوسیت ها می باشد.
slide70

GUT-ASSOCIATED LYMPHOID TISSUE (GALT)

This is comprised of:

* tonsils, adenoids (Waldeyer's ring)

* Peyer's patches

* lymphoid aggregates in the appendix and large intestine

* lymphoid tissue accumulating with age in the stomach

* small lymphoid aggregates in the esophagus

* diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut

Large aggregates of GALT have distinct B cell follicles and T cell areas. Antigen presenting accessory cells are also present.

Peyer's patches are large aggregates of lymphoid tissue found in the small intestine. Lymphocytes form domed follicles of B cells surrounded by T cells. Some epithelial cells have complex microfolds in their surfaces.

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Known as M (multi-fenestrated, arrangement) cells, they collect Ag. Peyer's patches facilitate the generation of an immune response within the mucosa. B cell precursors and memory cells are stimulated by Ag in Peyer's patches.

Cells pass to the mesenteric lymph nodes where the immune response is amplified.

Activated lymphocytes pass into the blood stream via the thorasic duct.

These cells then home in the gut and carry out their final effector functions.

HEVs are not present in Peyer's patches and the mechanism by which cells home in on mucosal sites is unknown. Cell surface molecules known as addressins may have a role.

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follicle-associated

epithelium

villi

M cell

lymphatic

network

Peyer’spatch

follicular DC

lamina

propria

T cells

B cells in

domed follicle

high

endothelial

venule

centroblast

B cells

gut lumen

ORGANIZATION OF GALT

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MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT)

In addition to the lymphoid tissue concentrated within the lymph nodes and spleen, lymphoid tissue is also found at other sites, most notably the gastrointestinal tract, respiratory tract and urogenital tract.

MALT consists of aggregates of lymphocytes, macrophages, DCs, and other accessory cells.

In the gut, these aggregates are scattered throughout the lamina propia, although Peyer’s patches

(which resemble lymph nodes in that they have germinal centers and B cell-rich follicles) are also present in the gut.

SKIN-ASSOCIATED LYMPHOID TISSUE (SALT)

Skin is an active participant in host defense. It has the capability to generate and support local immune and inflammatory responses to foreign Ags that enter the body via the skin. Cells of SALT include keratinocytes, Langerhans cells (immature DCs found in skin), intraepiethelial T cells, and melanocytes.

Langerhans cells form a continuous epidermal meshwork: they capture Ag, then migrate to draining lymph nodes, where they act as Ag-presenting cells.

The majority of T cells are found in the dermal layer of skin.

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Antigen presentation in skin infection

Langerhans cells

Epidermis

Skin

Interstitial (dermal) DC

Dermis

Denstritic cells undergo maturation upon antigen capture.

TLR-PAMP

TNF-, IL-1

Immature DC

Mature DC

Low surface MHC-II

MHC-II retained in lysosomes

(lamp is a lysosomal protein)

High surface MHC-II

High co-stimulation

Low co-stimulation (CD80, CD86)

Inefficient internalization of antigens

Active internalization of antigens

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Animal skin separates the inner world of the body from the largely hostile outside world and is actively involved in the defense against microbes.However, the skin is no perfect defense barrier and many micro organisms have managed to live on or within the skinas harmless passengers or as disease-causingpathogens.Microbes have evolved numerous strategies that allow them to gain access to the layers underneath the epidermis where they either multiply within the dermis or move to distant destinations within the body for replication.

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A number of viruses, bacteria and parasites use arthropod vectors, like ticks or mosquitoes, deliver them in to the dermis

While taking their blood meal. Within the dermis, successful pathogens subvert the function of a variety of Skin resident cells or cells of the innate immune System that rush to the site of infection.

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Immature DCs efficiently capture antigens.

DCs can internalize diverse antigens.

B cells only internalize antigens

that bind to BCR.

FcR, CR, Mannose receptors

phagocytosis

macropinocytosis

endocytosis

BCR

Endosomes/lysosomes

DC maturation decreases antigen uptake.

DCs internalized carbon particles.

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Inflammation induces DC maturation.

LPS

+

HEL

Immature DC

Immature DC

internalizes HEL.

Mature DC presents

HEL peptides / MHC complex

on cell surface.

9 hr

4 hr

22 hr

+LPS

HEL peptide

-LPS

HEL peptide/MHC II moves to cell surface after LPS treatment.

Mature DCs have higher levels of surface MHC-II than B cells and macrophages.

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Immature dendritic cells can retain antigens in endosomes/lysosomes.

Mature DC in lymphoid tissues

Immature DC in peripheral tissues

Cystatin C inhibits cathepsins to prevent

degradation of antigens and invariant chain.

Cystatin C level decreases during maturation.

Degradation of antigen and invariant chain

allows peptide loading and exit of MHC-II

from lysosomes.

Invariant chain retains MHC II in lysosomes.

Strong proteolytic activity in macrophage lysosomes cause excessive degradation of antigens.

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DC maturation increases surface expression of co-stimulatory molecules and MHC-I.

Co-stimulation

B7 and class I MHC move from ER to

cell surface.

(B7)

Immature DC

TNF-

Cell number

LPS

Mature DC

Co-localization of peptide and B7 with MHCII on cell surface

facilitates T cell activation.

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LYMPHOCYTE RECIRCULATION

Lymphocytes and some monos can recirculate between lymphoid and non-lymphoid tissues. This helps lymphocytes to be exposed to the antigens which they recognize and is valuable for the distribution of effector cells to sites where they are needed.

The recirculation is a complex process depending on interactions between the cells of the immune response and other cell types such as endothelial cells. Naive lymphocytes move from the primary to secondary lymphoid tissue via the blood..

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Activated lymphocytes move from the spleen, lymph nodes, and other lymphoid tissue (e.g., MALT) into the blood and then to other lymphoid and non-lymphoid tissues.

APCs may carry Ag back to lymphoid tissues from the periphery.

The complex patterns of recirculation depend on the state of activation of the lymphocytes, the adhesion molecules expressed by endothelial cells, and the presence of chemotactic molecules, which selectively attract particular populations of lymphocytes or macrophages

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Naïve T cells circulate between blood and

secondary lymphoid organs.

Afferent lymph

Efferent lymph

Lymph node

Efferent lymph

Lymphocytes

(B and T cells)

25-33% leukocytes

thymus

Peyer’s patch

Mucosal tissues

spleen

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T cells are recruited to secondary lymphoid tissues by chemokines.

Spleen white pulp

B cell follicle

CXCL13

CCL21

CCL21

CCR7

T cell region

B cell

CCL21

CXCL13

CXCR5

T cell: CCR7

CCL21

Lymph node

HEV

CCL21

B cell follicle

CXCL13

CCL21

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Inflammation induces DC migration into lymph node.

Peripheral tissue (skin)

Inflammation (TLR-PAMP, IL-1, TNF-) induces CCR7 expression.

Langerhans cells

Interstitial DCs

Monocyte-derived DCs

Afferent lymphatic vessel

CCL21

CCL19

CCL21

Lymph node

Macrophages do not migrate to lymphoid tissues.

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inflammation

DC

skin

DC (blue)

Skin draining lymph node

DC

Skin draining LN

B cell follicle (CD19 staining)

T cells (brown, CD3 staining)

DCs migrating through

lymphatic vessels.

Langerhans cells (blue, langrin staining) from skin

localize in T cell area.

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Antigen presentation by migrant and resident DCs in lymph node

Migrant DCs capture antigens

locally at low concentrations.

Antigen transported to lymph nodes

through afferent lymph

Particular antigen may need to

be processed and presented by

migrant DCs.

Later and persistent T cell

activation

Resident DCs capture lymph-borne antigens

for initial T cell activation

Spleen white pulp

B cell follicle

CXCL13

B cell follicles

T cell

T cell region

Langerhans cells, myeloid DCs (CD11c+, CD11b+) are the most

potent activators of CD4 T cells.

Blood-borne antigens are captured

by DCs in spleen

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No antigenic challenge

Antigenic challenge

T cells

12-18 hours

TCR recognizes antigen.

B cells

24 hours

Activation and proliferation

Secondary lymphoid organs facilitate the encounter

of rare antigen-specific lymphocytes with antigen.

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The antigen receptor molecules• There are three groups of molecules that specifically recognize foreign antigen for the adaptive immune system. • B cell receptor(BCR or the antibody)• T cell receptor (TCR)• Major histocompatibility complex(MHC), this cluster of genes is known as human leukocyte antigen (HLA).

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MHC• This group of antigen receptor is represented by the proteins encoded by the MHC genes (located on chromosome 6) and it is known as Human leukocyte antigen (HLA). • There are two main classes of molecules, which were initially named because of their role in tissue (histo-) graft rejection (compatibility). • Class I MHC molecules are found essentially on all cells except RBCs, and• Class II MHC molecules are found chiefly on APC (B cells and Monocytes).• The main function of MHC molecules is to present antigens to T cells.