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.
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.
OVERVIEW OF THE IMMUNE SYSTEM
Organized 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.
Lymphatic system
Immune system organs and
tissues
(Lymphoid tissue)
LOCATION
OF MAJOR
LYMPHOID
ORGANS
THROUGHOUT
THE BODY
(not truly a lymphoid
organ, but the source
of IS progenitor cells)
Lymphoid tissues:
Are the sites where the ;
– Generation,
– Maturation,
– Habitation
and
– Activation of the immune cells
take place.
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.
lymphocyte from blood smear,
Wright-Giemsa stain, 1000x
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.
T versus B Cells
Ag receptor
Ig
T cells
B cells
TCR related to Ig
BCR is membrane-bound
but not Ig
Ag recognition in context of MHC
on APC or accessory cells
can recognize Ag alone
Functional
subsets
Th (helper) and
Tc (cytolytic)
subsets of B cells not
different in function
Secrete
Cytokines
Ig (as Ab) and cytokines
Surface
markers
CD4 and CD8
(among many others)
Ig (among many others)
When Agthen
activated
Become (proliferating)
Become lymphoblasts,
lymphoblasts
become plasma cells
Costimulation
required?
Yes
No
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.
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.
macrophage in tissue, H&E stain, 400x
mono in blood smear Wright
Giemsa, 1000 x
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.
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.).
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.
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,
plasmacytoid DCs (periphery
& spleen) and myeloid DCs
(bone marrow). So far no
major functional differences
noted.
LPS-activated DCs
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
GRANULOCYTES
Polymorphonuclear 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.
azurophilic staining of PMNs
PMN, note tri-lobed nucleus
Wright-Giemsa, 1000x
Mono
Comparison of mono to PMN
PMN
BASOPHILS AND MAST CELL
Have basophilic granules, which contain
mediators, especially of allergic responses.
Basophils circulate, mast cells found in tissue.
Basophil
Degranulating
mast cell
intact
mast cell
mast cells
EOSINOPHILS
Have granules that stain red with eosin. Mediate late phase of allergic
response, active in immune response to parasites & tumors (antibodydependent cell-mediate cytotoxicity). Granules contain toxic proteins
of high pH.
Eosinophil
eosino
Eosinophil
phil
PMNs
Comparison of PMNs to
eosinophil
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.
Hematopoietic stem cell
Stromal stem cell
Primary lymphoid tissues
The 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.
‫مغزاستخوان ‪ :‬سه فونکسیون به عهده دارد ‪:‬‬
‫مرکزتولید اکثررده های سلولی مختلف خونی می باشد ‪ .‬درمغزاستخوان‬
‫‪ Stem Cell‬لنفوئید ها را می سازد ‪ .‬ازسلول اخیر سلول های ‪T‬‬
‫لمفوئید ‪ B ،‬لمفوئید ‪ NK Cell ،‬یا سلول های کشندۀ طبیعی و ‪K‬‬
‫‪ Cell‬ها 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 پالکت را می سازند‪.‬‬
‫مونوسیت ها که سازندۀ ماکروفاژها هستند نیزاز ‪Myeloid cell‬ها‬
‫منشأ می گیرند‪.‬‬
‫دندریتیک سل ها( ‪ )dendritic cell‬که ماکروفاژهای تخصص یافته‬
‫هستند نیزازاین سلول ها منشأ می گیرند و ماست سل ها ‪mast cells‬‬
‫نیز ازاین سلول ها مشتق گردیده اند‪.‬‬
‫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 از‪ %50‬آنتی بادی ها درمغزاستخوان تولید‬
‫می شوند که بیشتر ازنوع ‪ IgG‬می 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.Com‬محل تشکیل سلول های خونی و بخش‬
‫…‪ V.Com‬محل عروق خونی ‪ ،‬سینوس های خونی و ‪RBC‬ها‬
‫ونیزمغزاستخوان است‪.‬‬
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.
‫هورمون های تیموس ‪:‬‬
‫تیموس هورمون های مختلفی تولید می کند وبعنوان یک غدۀ آندوکرین داخلی تلقی‬
‫می شود ازجمله تیموزین ‪ Thymosine‬که دارای سه تیپ آلفا ‪ ،‬بتا و گاما می‬
‫شود وهرکدام نیزگروهی فرعی دیگری دارند ‪.‬‬
‫اثر این هورمون القاء ظهورآنزیم ‪Terminal Deoxynucleotidyl ( T.D.T‬‬
‫‪ ) Transferase‬وهمچنین ظهور ‪Receptor‬گلبول قرمز برسطح لنفوسیت های‬
‫‪ T‬که اصطالحا ً به آن ‪Cd2‬می گویند می باشند‪.‬‬
‫تیمو پوئی تین ‪ : Thymopoetin‬دو نوع دارد ودرتنظیم پاسخ های ایمنی‬
‫وافزایش جمعیت لنفوسیت های مهارکننده ( ‪ )T. Suppressor‬دخالت دارد که‬
‫دربیماری های اتوایمیون ‪ Auto Immune‬ایفای نقش می نماید‪.‬‬
‫‪ : Thymic humoral factor‬این هورمون می تواند تمایز لنفوسیت های ‪ T‬را‬
‫تشدید نماید و صالحیت لنفوسیت های ‪ T‬را درموش های که تیموس آن ها را‬
‫برداشته اند اعاده نماید‪.‬‬
‫‪ : Factor Thymic serige‬بوسیلۀ سلول های اپی تلیال تیموس تولید می شود‬
‫و باعث القاء ظهورآنزیم های سطحی لنفوسیت های ‪ T‬می شود‪.‬‬
‫تیموس دارای دو بخش است ‪:‬‬
‫بخش قشری یا ‪ : Cortex‬ازتعداد زیادی سلول به نام‬
‫‪ Thymocyte‬تشکیل یافته است که منشاء آن ها از ‪Pre‬‬
‫‪ Thymocyte‬بوده که این نیز به نوبه خود از ‪Stem Cell‬‬
‫درمغزاستخوان منشأ می گیرد‪ .‬این سلول ها دائما ً درحال تقسیم وتمایز‬
‫بوده وتعدادی از آن ها ازبین می رود وبخشی از آن ها که الزم است‬
‫تمایزیافته و وارد مدوال ‪ Medulla‬می شود‪.‬‬
‫بخش مرکزی یا ‪ : Medulla‬این بخش ازبافت اپی تلیال تیموس‬
‫تشکیل یافته است ودراین بخش اجسامی قراردارند که بنام اجسام‬
‫هاسل یا ‪ Hassal body‬نام 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 ‪ Nurse Cell‬نامیده می شوند‬
‫‪.‬‬
‫اجسام هاسل ‪ :‬بیش از‪ %90‬لنفوسیت 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 distrophy‬دیستروفی عضالنی ) که درجریان‬
‫اختالالت 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 الیۀ ‪ ،‬ممبران بازال ‪ Membrane basal‬یا‬
‫‪ Basment membrane‬می باشد که این وضعیت همراه وجود‬
‫ماکروفاژها مانع از ورود آنتی ژن به داخل تیموس می شود ‪ .‬لذا‬
‫تیموس یک عضو ‪ Thymic blood barrier‬می باشد ‪ ،‬بدین سبب‬
‫آموزش لنفوسیت ها درداخل تیموس بدون حضورآنتی ژن های خارجی‬
‫صورت می گیرد‪.‬‬
Lymphoid tissues-continued
THYMUS young
Cortex - dark
Connective
tissue
Lobules
Medulla light
Hassall’s thymic
corpuscle
round, red, layered
Packed lymphocytes
(thymocytes)
PRINCIPAL THYMIC CELLS
EPITHELIORETICULAR CELL
NA‫د‬VE
LYMPHOCYTES
(THYMOCYTES)
desmosome
MF
disposing of unapproved thymocyte
Haematopoesis
Dendritic cells (DC)
B cells
CLP
Myeloid DC (CD11c+, CD11b+, CD8-)
T cells
Langerhans cells (skin)
(CD11c+, CD11b+, CD8+/-, Langerin)
Dendritic cells
HSC
Lymphoid DC (CD11c+, CD11b-, CD8+)
CMP
Monocytes
Plasmacytoid DC (CD11c+, B220+)
granulocytes
Monocyte-derived DC
(CD11c+/-, CD11b+, CD8-)
inflammation
erythrocytes
Megakaryoctes
Lymphoid progenitor
Myeloid progenitor
Monocytes progenitor
Stem cell differentiation
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.
Peyers Patch ‫پالک های پی یر‬
‫بعضی این ارگان را معادل بورس درپرندگان می دانند که‬
‫در روی روده ها قرار دارد وشامل دو قسمت است ‪:‬‬
‫الف ) درناحیۀ ‪ Ieujenum‬قراردارد‬
‫ب ) درناحیۀ ‪ Illeum‬و ‪ Secum‬قراردارد‪.‬‬
‫پالک های پی یر برروی ایلوئوم درهرساعـت ‪3600000‬‬
‫لنفوسیت تولید می کند که فقط ‪200000‬باقیمانده وبقیۀ آن‬
‫ازبین می روند درحالیکه پالک 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 ثانویه می باشند که مهمترین آن ها طحال است‪.‬‬
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 (cortex, paracortex, and medulla).
Cortical nodules
(follicles)
Cortex
Medullary
sinuses
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).
Sub-capsular
Sinus
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.
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).
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.
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
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.
Activated T cells then pass into the
circulation to reach peripheral sites.
Accessory cells: Interdigitating cells are
numerous in the paracortex and act as Agpresenting cells.
Medulla
The medulla is comprised of:
* large blood vessels
* medullary cords
* medullary sinuses
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.
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.
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.
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.
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.
INSIDE THE SPLEEN
Red pulp
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.
INSIDE THE SPLEEN CONTINUED
Capsule
Trabecula
Primary
follicle
Vascular
sinusoids
Marginal
zone
White pulp
Periarterial
lymphatic
sheath (PALS)
Germinal center
Red pulp
Vein
Artery
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.
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫طحال ‪: Spleen‬‬
‫بزرگترین ارگان لنفاوی ثانویه است که سرراه گردش خون وجود دارد‬
‫ودارای دو قسمت است ‪:‬‬
‫‪ -1‬پولپ سفید ‪ -2 White Pulpe‬پولپ قرمز ‪Red Pulpe‬‬
‫سطح طحال ازبافت همبندی سختی پوشیده شده است که ترابکوالهایی 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 ابتال‬
‫به لیشمانیا یا ناهنجاری های گلبول های قرمز که موجب بزرگی طحال می‬
‫شود‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫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 ‪:‬‬
‫‪ -1‬محل عمدۀ تولید آنتی بادی‬
‫‪ -2‬محل عمده برای شناسایی و عرضۀ آنتی ژن ‪ ،‬تولید پاسخ با همکاری‬
‫لنفوسیت های ‪ B‬و‪ T‬وماکروفاژها‬
‫محلی برای جذب مجدد آهن ناشی ازانهدام ‪RBC‬ها‬
‫محل انهدام لنفوسیت های پیر و گلبول های قرمزپیر و لکوسیت های پیر‬
‫احتماالً 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.‬‬
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.
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.
ORGANIZATION OF GALT
M cell
villi
follicle-associated
epithelium
lymphatic
network
lamina
propria
high
endothelial
venule
Peyer’s
patch
T cells
gut lumen
follicular DC
B cells in
domed follicle
centroblast
B cells
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.
SALT
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
Low surface MHC-II
MHC-II retained in lysosomes
(lamp is a lysosomal protein)
Mature DC
High surface MHC-II
High co-stimulation
Low co-stimulation (CD80, CD86)
Inefficient internalization of antigens
Active internalization of antigens
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 skin
as harmless passengers or as disease-causing
pathogens.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.
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.
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.
Inflammation induces DC maturation.
LPS
+
HEL
Immature DC
Immature DC
internalizes HEL.
4 hr
9 hr
22 hr
HEL peptide
+LPS
Mature DC presents
HEL peptides / MHC complex
on cell surface.
-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.
Immature dendritic cells can retain antigens in endosomes/lysosomes.
Immature DC in peripheral tissues
Cystatin C inhibits cathepsins to prevent
degradation of antigens and invariant chain.
Invariant chain retains MHC II in lysosomes.
Mature DC in lymphoid tissues
Cystatin C level decreases during maturation.
Degradation of antigen and invariant chain
allows peptide loading and exit of MHC-II
from lysosomes.
Strong proteolytic activity in macrophage lysosomes cause excessive degradation of antigens.
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)
Cell number
Immature DC
TNF-
LPS
Mature DC
Co-localization of peptide and B7 with MHCII on cell surface
facilitates T cell activation.
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..
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
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
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
CXCR5
T cell: CCR7
CXCL13
CCL21
Lymph node
HEV
B cell follicle
CCL21
CXCL13
CCL21
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
CCL19 CCL21
CCL21
Lymph node
Macrophages do not migrate to lymphoid tissues.
inflammation
DC
skin
DC (blue)
Skin draining lymph node
DC
Skin draining LN
T cells (brown, CD3 staining)
B cell follicle (CD19 staining)
DCs migrating through
lymphatic vessels.
Langerhans cells (blue, langrin staining) from skin
localize in T cell area.
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
(CD11c+,
Langerhans cells, myeloid DCs
potent activators of CD4 T cells.
CD11b+)
are the most
Blood-borne antigens are captured
by DCs in spleen
No antigenic challenge
T cells
12-18 hours
Antigenic challenge
TCR recognizes antigen.
B cells
24 hours
Activation and proliferation
Secondary lymphoid organs facilitate the encounter
of rare antigen-specific lymphocytes with antigen.
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).
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.
Antigen recognition molecules