Cells and Lymphoid Tissue Maturation, Activationvlm.ub.ac.id/pluginfile.php/41455/mod_resource... · •The organs that regulate the maturation of lymphocytes develop early in fetal

Cells and Lymphoid Tissue;Maturation, Activation, and

Regulation of Lymphocyte

19 Februari 2020

drh. Sruti Listra Adrenalin, M.Sc.

Origin of Cells of the Immune System

• Pluripotent hematopoietic stem cells of the bone marrow.

• Most important cells are the lymphocytes originate from progenitor cell in the bone marrow.

• T lymp: cellular immune response.

• B lymp: produce ab (humoral immune response).

• NK cell: express some feature of myeloid cells.

… Origin of Cells of the Immune System

… Origin of Cells of the Immune System

Defense Mechanisms Against Infections

• Immune system: protect the organism against infection.

• Innate immunity: deployed shortly after the body has been invaded by a pathogen hours.

• Main mechanism: phagocytosis recognition of typical molecular structures that are shared among dif. pathogen consist: phagocytic cells, blood proteins, NK cells.

• Adaptive immunity: based on the presence of receptors are highly specific for certain epitopes of the pathogens specific response (days – weeks).

• Receptors:T lymp, some B lymph/ ab produced by B lymph.

… Defense Mechanism Against Infections

Immune Cells

… Immune Cells

• Neutrophil (PMN cell)

Professional phagocyte cell nonspecific immune response.

• Eosinophil

Important in parasites infection & allergy.

• Basophile & Mast cell

Important in parasites infection & allergy; degranulation of these cells after bridging with allergen releasing of vasoactive mediators.

… Immune Cells

• Monocytes & macrophages

Professional phagocyte cells, have multifunction: in RES as APC(antigen presenting cells) processing and presenting antigen to Tcells; produce sitokin; very important in cellular I.R.

• Dendritic cells

As APC, most present in lien & lymph nodes containing T cell.

Comparison of Primary and Secondary Lymphoid Organs

Primer Sekunder

Asal Ektoendodermal junction atau endoderm Mesoderm

Waktu perkembangan Awal kehidupan embrio Akhir kehidupan fetus

Persistensi Involutes after puberty Persist in adult

Effect of removal Loss of lymphocyte No or minor effect

Respon terhadap antigen Tidak ada respon Sangat reaktif

Contoh Thimus, bursa, peyer patches, sumsum tl Limpa, kel. Getah bening

Lymphoid System

Evolution

… Evolution

… Evolution

Kelompok

Innate

immunity

(non spesifik)

Adaptive

immunity

(spesifik)

Invasion-

induced

protective

enzymes and

enzyme cascade

FagositosisAntimikrobial

peptide

Pattern-

recognition

resptor

Graft

rejectionSel B dan T Antibodi

Higher plant + - + - + + - - -

Hewan invetebrata

Porifera (sponge) + - ? + ? ? + - -

Annelide (cacing tanah) + - ? + ? ? + - -

Artropoda (serangga,

krustasea)+ - + + + + ? - -

Hewan vertebrata

Elasmobranchs (ikan

berkartilago contoh

shark, rays)

+ + + +Equivalent

agent+ + + +

Teleost fish dan bony fish

contoh salmon, tuna + + + + Probable + + + +

Amfibi + + + + + + + + +

Reptil + + + + ? + + + +

Unggas + + + + ? + + + +

Mamalia + + + + + + + + +

Primary Lymphoid Organs

• The organs that regulate the maturation of lymphocytes develop early in fetal life.

• Immature lymphocytes migrate from the bone marrow primary lymphoid organs where they mature.

• Lymphocytes T and B based on the organ in which they mature T cells (thymus).

• B cells (dif. Organs depending on species) B. fabricius (birds), bone marrow (primates, rodent), intestinal lymphoid tissue (rabbits, ruminant, pig).

• Not enlarge in response to antigenic stimulation.

… Primary Lymphoid Organs

1. Thymus

2. Bone Marrow

3. Bursa of Fabricius

4. Peyer’s Patches

5. Lymphoglandular Complexes

Thymus

• Located: Thoracic cavity in front of and below the heart.

• Structure: maximal size at birth and involutes, and impossible to see in adult animals.

• Function: Maturation T lymphocytes from bone marrow (primary development site).

Bone Marrow

• Within the bone marrow is a population of primordial stem cells production of the various haemopoietic lineages (erythroid, platelet, myeloid), including the lymphoid cells.

• Lymphoid B dan T immature maturation in further primary lymphoid tissues elsewhere in the body.

• The primary lymphoid organ for B-cell development (especially Group II mammals).

• B lymphocytes are involved in the production of antibody, which comprises the humoral immune response.

Bursa Fabricius (Birds)

• Located: above the cloaca.

• Greatest size 1-2 weeks after hatching.

• Function: maturation, differentiation site for the cells of the ab-forming system (immature B cells produced in the bone marrow migrate to the bursa).

• Immature B cells proliferate rapidly 90-95% die by apoptosis (negative selection of self-reactive B cells) maturation emigrate to secondary lymphoid organs.

• Bursin (tripeptide: Lys-His-glycylamide): the most important hormone that activates B cells, not T cells.

Peyer’s Patches

• Located:in the walls of the small intestine.

• (Group I) ruminants, pigs, horses, dogs, humans: 80-90%: found in the ileum.

• (Group II) rabbits, rodents: random intervals in the ileum and jejunum not develop until 2-4 weeks after birth and persist into old age.

• Function: rapid B cells proliferation (95% apoptosis) release into the circulation produce ab.

• Group I: process of B-cell maturation.

• Group II: lack an ileal Peyer’s patch.

Lymphoglandular Complexes

• Found in the wall of the large intestine & cecum horse, ruminant, dog, pig.

• Lined by intestinal columnar epithelium containing goblet cell, intraepithelial lymphocytes, M cell.

• Presence many M cells.

• Contain many plasma cells sites of ab prod.

• Similar to avian bursa.

Secondary Lymphoid Organs

• Encapsulated:

1. Lymph Nodes

2. Spleen

• Unencapsulated:

1. MALT

Lymph Nodes

• Structure of lymph nodes spherical follicles

(B cells) within a surrounding paracortex (T cells).

• Pemb. Limfatik aferen Sinus subkapsular

medullary sinus pemb. Limfatik eferen.

Spleen

• Encapsulated organ.

• Red pulp (reservoir of blood/ dendritic cell,

B cell, macrophage, erythrocyte) white pulp

(splenic lymphoid tissue/ T cell).

• T cells form a cylindrical surround to such

vessels PALS.

• B cells follicles.

… Spleen

• Fungsi:

1. Respon imun dari ag asal darah.

2. Mikroorganisme dibersihkan oleh makrofag dlm limpa.

3. Tempat fagositosis mikroorganisme yg dilapisi Ab (opsonisasi).

Unencapsulated Lymphoid Tissue

• Largely scattered throughout the body mucosal surfaces.

• MALT (mucosa-associated lymphoid tissue) GALT, BALT,

NALT, CALT.

• GALT organized by Peyer’s patch induce and the

end effect of immune response production of IgA.

Mucosal Lymphocyte Recirculation

… Secondary Lymphoid Organs

• Ab could produced in the bone marrow, tonsils, lymphoid tissue.

• Ag trapped in the liver, spleen, bone marrow.

• Ab (primary immune response) largely produced in the spleen, lymph nodes

… Secondary Lymphoid Organs

Lymphocyte

… Lymphocyte

• The cells responsible for mounting the acquired immune response T, B cell ab mediated & cell mediated.

• Structure: small (7-15µm), round cell w/ nucleus (surrounded by cytoplasm containing mitochondria, ribosomes, Golgi apparatus).

• Mainly found in lymp. organs, blood,

scattered under mucosal surface.

• Diverse of cell subpopulation

identified by characteristic cell surface

molecules, behavior.

… Lymphocyte

• Within lymphoid tissue, blood and lymphatic fluid small and large lymphocytes (lymphoblasts) and plasma cells.

• Small lymphocytes T/ B cells naif/ memory cells.

• Large lymphocytes (lymphoblasts): active cells that stimulated by antigen .

• Plasma cells: late stage of development of B lymphocytes secrete high immunoglobulin

… Lymphocyte

The Identifying Features of T & B Cells

Property B cell T cell

Perkembangan di- Bone marrow (pendewasaan), bursa

fabrisius, Peyer’s patches

Timus (dan pendewasaan)

Fungsi Proteksi mikroorganisme

ekstraseluler

Proteksi mikroorganisme intraseluler

Distribusi Lymph node cortex,

Splenic follicle

Lymph node paracortex

Spleen periarteriolar sheath

Sirkulasi Tidak Ya

Reseptor ag BCR – Imunoglbulin/ ab TCR – protein heterodimer

Dihubungkan dengan CD3, CD4, atau CD8

Ag permukaan yg penting Ig CD2, CD3, CD4, atau CD8

Ag recognized Free foreign proteins Protein asing diproses pd MHC antigen

Pengenalan MHC Tidak Ya

Sel progeny Sel plasma, sel memori Sel T efektor, sel T memori

Produk sekresi Ig/ ab Sitokin

… Lymphocyte

• T cells leave the thymus accumulate in paracortex lymph nodes, periarteriolar lymphoid sheath spleen, interfollicular Peyer’s patches (40-80% in blood).

• B cells from bone marrow/ bursa mature within Peyer’s patches/ bone marrow migrating to the secondary lymphoid organs found in cortex lymph nodes, follicle Peyer’s patches & spleen, white pulp marginal zone of spleen (10-50% in blood) plasma cell.

• NK cells (large, contain an extensive cytoplasm & abundant cytoplasmic granules).

• NK cells: non specific action, have no surface marker like T & B cells.

… Lymphocyte

• Lymph cells subpopulation each has function/ chemical name: Cluster of Differentiation (CD).

• Ex. FcαR (CD89), iL-6R (CD126), L-selectin (CD62L).

• B cells as APC express MHC class II molecules on the surface.

• Molecules that regulate lymphocyte function: cytokine, ab, complement receptor.

Class of LymphocyteKelas Fungsi Reseptor antigen dan

spesifisitas

Selected marker Persentase total limfosit (manusia)

Darah Lymph nodes Limpa

αβ T limfosit

Limfosit T helper CD4+ Diferensiasi sel B (imunitas humoral)

Aktivasi makrofag (cell-mediated

immunity)

αβ heterodimer

Berbagai macam peptida kelas II

Kompleks MHC

CD3+, CD4+, CD8- 50-60* 50-60 50-60

Limfosit T sitotoksik CD8+ Membunuh sel yang terinfeksi

mikroba, membunuh sel tumor.

αβ heterodimer

Berbagai macam peptida kelas I

Kompleks MHC

CD3+, CD4-, CD8+ 20-25 15-20 10-15

Sel T regulator Menekan fungsi sel T lain (regulasi

sistem imun, maintenance dari self-

tolerance)

αβ heterodimer CD3+, CD4+, CD25+ (paling

umum, tetapi terdapat juga

fenotipe lainnya)

Jarang 10 10

Limfosit T γδ Helper and sitotoksik function (innate

immunity)

Γδ heterodimer

Spesifisitas terbatas untuk antigen

peptide dan non peptide

CD3+, CD4, dan variable CD8.

Limfosit B Produksi antibody (imunitas humoral) Antibodi permukaan.

Diverse spesifisitas untuk seluruh tipe

molekul.

Fc reseptor, MHC kelas II, CD 19,

CD 21.

10-15 20-25 40-45

Sel natural killer Membunuh sel yang terinfeksi virus

atau sel yang rusak (innate immunity)

Various activating and inhibitory

receptors.

Spesifitas terbatas untuk MHC atau

MHC-like molecules.

CD 16 (Fc reseptor untuk IgG) 10 Jarang 10

Sel NKT Menekan atau mengaktifasi respon

imun innate dan adaptif.

αβ heterodimer

(spesifisitas terbatas untuk glikolipid

kompleks CD 1)

CD 16 (Fc reseptor untuk IgG),

CD3

10 Jarang 10

Development of T and B Lymphocyte

Lymphocyte Maturation

… Lymphocyte Maturation

Activation of Lymphocyte

… Lymphocyte Maturation

• Sel T, B dari prekursor yg sama, diproduksi dlm bone marrow.

• Sel B maturasi di bone marrow, progenitor sel T migrasi &mature di timus

• Sel T,B berproliferasi atas pengaruh sitokin (IL-12 yg me ↑ jmlh selmature).

• Pematangan limfosit tjd mll seleksi. Seleksi pematangan primertjd dlm limfoid primer. Sel diseleksi mll interaksi dg mol MHC.

Development and Activation of Lymphocyte T

… Development and Activation of Lymphocyte T

• Sel T diproduksi di Bone Marrow, & perkembangan di Timus.

• Sub bagian anatomi timus:

cortical thymocytes di kortex perkembangannya akan berpindah

dr 1 area ke area lain. Sel T progenitor akan masuk ke Timus mll High

Endothelial Venule (HEV) & migrasi ke daerah Subcapsular sel T

mengekspresikan reseptor di kortex, ekspresi sinyal beda, tjd interaksi TCR

& MHC Sel T progenitor/timosit akan memulai proses maturasi mll

pengaturan gen T cell receptor.

• Tjd T cell double neg: sel T tdk mengekspresikan CD4 & CD8 Kortex,Medulla Mengekspresikan CD4 & CD8 Double pos.

• Di kortex tjd pos selection.

… Development and Activation of Lymphocyte T

• Pos selection untuk menentukan apakah TCR CD4/CD8 dapat berikatandgn MHC I/II. Sel T yg mengenali MHC I akan menerima sinyal pertahanan& sinyal maturasi shg dapat mempertahankan ekspresi CD8 & stop ekspresi CD4. Berlawanan dgn MHCII, diperantarai oleh Thymic Cortical Epithelia Cells.

• Neg selection : mengeliminasi sel T yg mengikat kuat pada self protein, kmdn tjd apoptoss. Mll positive and negative selections, mature T cells menginduksi mekanisme effector utk mengeliminasi benda asing (bukanbag. Dari ag permukaannya). Sehingga Peptida yg terikat pada MHC menentukan final T-cell reseptor.

• Bone marrow Timus Double -, Double + + selection, - selection.

Maturation of T cells

… Development of Mature T Cells

B Cells Activation

B Cells Development

Lymphocyte Recirculation

Immune Response

(1) Adanya infeksi akan Inisiasi respon imun innate.

(2) Sel imun innate menjadi mature dan berdiferensiasi bermigrasi ke lymph nodus.(3-5) APC menginduksi responimun adaptif , mengaktifasi sel T mjd sel efektor danberdiferensiasi dari sel T menjadi sel memori.

(6) Sel B naif berdiferensiasi mjd ab-sekresi plasma sel dansel B memori diikuti aktivasi oleh sel T helper CD4+

(7) sel T CD4+ yang teraktivasi akan mengaktifkan makrofag.

(8) Antibodi dapat meningkatkan fungsi efektor sel innate,

(9) dan juga menetralkan agen pathogen.

(10) Sel T sitotoksik secara langsung membunuh jaringan/ sel yang terinfeksi secara molekuler dan sinyal kimia,

(11) dan juga menginduksi sel yang terinfeksi/ fagosit untukmembunuh pathogen intraseluler, atau menghambatreplikasi pathogen.

References

• Day, M.J., Schultz, R.D. 2014. Veterinary Immunology Principles and Practice 2nd Edition. CRC Press.

• Gers-Rudiger, B., Pezzutto, A., Wirth, J. 2003. Color Atlas of Immunology. Stuttgart German.

• Tizard, I.R. 2004. Veterinary Immunology An Introduction 7th

Edition. Saunders.