HC5: B- and T-cell generation and diversity
Diverse repertoire
A diverse repertoire is necessary because humans are exposed to many different pathogens:
- Innate immunity can react to some constant properties of pathogens
- Adaptive immunity should respond to all possible pathogens, previously encountered and new
- Adaptive immunity shows a high degree of antigen specificity
- Adaptive immunity shows memory and is able to improve upon re-exposure
Antigen specificity:
B- and T-cells play a very important part in adaptive immunity. The difference between B-cells and T-cells is obvious:
- B-cells: host defense against extracellular pathogens
- T-cells: host defense against intracellular pathogens
Both cells are characterized by receptors on the surface which have specificity for one antigen → one cell has one specificity. This makes it possible for cells to respond do different pathogens.
B-cell receptors and secreted antibodies
Immunoglobulin:
Antibodies are also known as immunoglobulin (Ig). They are large, Y-shaped proteins produced by B-cells to neutralize pathogens. Antibodies recognize unique molecules of the pathogen → antigens. Antibodies can occur in 2 physical forms:
- Soluble form: has been secreted from the cell to be free in the blood plasma
- Membrane-bound form: the B-cell receptor
Every B-cell has a B-cell receptor → a surface immunoglobulin protein which is attached to the membrane of the B-cell. The B-cell receptor has a transmembrane region with which it signals to B-cells. When an antigen binds to the immunoglobulin, it will start producing soluble antibodies → the final antibodies present in circulation.
Clonal selection:
Clonal selection has 2 main functions:
- Generate a large variety of lymphocytes
- Select and expand the cell with wanted specificity
Clonal selection makes it possible for the immune system to respond to things it hasn't dealt with before.
During clonal selection, a large variety of B-cells is generated out of which the correct cell is selected:
- A precursor cell makes many different cells which prepare the body for every threat that may be present
- There are lymphocytes with receptors for many different antigens
- During infection, lymphocytes with receptors that recognize the antigen give an activation signal
- The receptors form crosslinks with the antigen
- The lymphocytes with the correct receptor proliferate and differentiate
- The lymphocytes give effector cells that terminate the infection
This is peculiar, because one cell has one specificity, and one gene is one protein. This would mean that an unlimited amount of genes is necessary to be able to have receptors for every antigen.
Antibody properties:
B-cells secrete antibodies of the same specificity as the membrane-bound immunoglobulin. The immunoglobulin/antibody is a central molecule of the B-cell. It consists of:
- 2 heavy chains and 2 light chains
- N-termini and C-termini
- The C-termini attach the antibody to the plasma membrane
- Disulfide bonds → the heavy and light chains are covalently bound to each other
- A constant region and variable region
- The constant region is the same for every immunoglobulin
- The variable region is specific for every immunoglobulin → it contains the antigen binding site
The gene loci for Ig heavy chain and Ig light chain are composed of different building blocks:
- V-genes: variable genes
- D-genes: diversity genes
- D-genes are only present in the heavy chain
- J-genes: joining genes
- The first chromosome
Antibody generation:
The diversity is created by there being more/less V-, D- and J-genes in different heavy- and light-chains. By combining different components of germline DNA, a variable region which gives high specificity for an antigen is made:
- Germline DNA is DNA that is present in every cell
- When a B-cell wants to make antibodies, it starts to recombine its DNA
- 1 V-gene, 1 J-gene, 1 constant region and in case of a heavy chain 1 D-gene are joined together in a unique way for every B-cell
- The DNA → RNA → protein route is followed
- A polypeptide chain is created → the immunoglobulin molecule
The process makes it possible for the body to make a huge variety proteins.
Soluble antibodies:
Every antibody produced can be connected to the original B-cell. There is a sequence which can attach for example an IgM molecule to the plasma membrane. At mRNA level, the B-cell can make a soluble molecule when it lacks the tail with which it is made membrane-anchored → soluble antibodies are produced.
Selection points:
This process takes place in the bone marrow → both the precursor cells and B-cells are developing. To ensure that the correct cells are made, there are a few selection points during the process:
- Repertoire assembly: generation of diverse and clonally expressed B-cell receptors in the bone marrow
- Negative selection: alteration, elimination or inactivation of B-cell receptors that bind to components of the human body
- Positive selection: promotion of a fraction of immature B-cells to become mature B-cells in the secondary lymphoid tissues → B-cells need to be structurally functional and have a correct antibody
- Searching for infection: recirculation of mature B-cells between lymph, blood and secondary lymphoid tissues
- Finding infection: activation and clonal expansion of B-cells by pathogen-derived antigens in secondary lymphoid tissues
- Attacking infection: differentiation to antibody-secreting plasma cells in secondary lymphoid tissue
T-cell receptor
The T-cell receptor, like the B-cell receptor, is transmembrane-bound. It also has constant and variable regions and has an antigen binding site at the top of the molecule. The biggest difference between B-cell and T-cell receptors is the way they recognize antigens:
- B-cells are able to recognize everything that they encounter
- T-cells recognize certain peptide fragments produced after degradation of pathogens
MHC-molecules:
T-cell receptors recognize an MHC-molecule which is presenting a peptide:
- Pathogens are degraded in the cell
- An MHC-molecule presents a peptide
- The T-cell receptor recognizes the antigen MHC-complex
There are 2 kinds MHC (major histocompatibility genes)/HLA (human leukocyte antigens) molecules. Both molecules have a groove in which the peptide is presented and are very polymorphic → there is a huge variation in MHC molecules:
- MHC class I
- Made out of 1 chain with a common factor
- Intracellular antigens
- MHC class II
- Made out of 2 chains
- Presents extracellular proteins
For there to be a response, the T-cell receptor has to recognize both the MHC-molecule and the peptide → the combination has to be correct for there to be proper recognition.
Generating diversity in T-cells and selection:
A T-cell receptor is formed out of an a- and b-chain:
- The a-chain is similar to the light-chain in immunoglobulins → only has V- and J-domains
- Located on chromosome 14
- The b-chain is similar to the heavy-chain in immunoglobulins → has V- and J- and D-domains
- Located on chromosome 7
The thymus is a small organ located near the heart. It is largest during infancy. Because a T-cell receptor only sees peptides in the context of MHC-molecules, it has to undergo a special process in the thymus before it is mature:
- T-cell precursors travel from the bone marrow to develop in the thymus
- The progenitor cells receive signals → proliferation
- These cells are still precursor cells and are considered as "double-negative" → they lack 2 essential markers for selection
- The precursor cells start rearranging the b-genes of their DNA
- Check point: everything which is useless or doesn't make sense after the rearrangement is eliminated
- Proliferation continues and the a-chain is rearranged
- Check point: it is determined whether the cells are useful or not
- Mature T-cells leave the thymus and travel to secondary lymphoid tissues
T-cell selection:
The thymus has specialized cells which can interact with developing T-cells → thymocytes. After the T-cells have developed, positive and subsequent negative selection of T-cells in the thymus occurs:
- Positive selection: T-cells which have developed and have a receptor try to interact with epithelial cells in the thymus, which express MHC-molecules
- If the T-cell is unable to recognize the MHC + peptide it will not get a signal → cell death
- If the T-cell is able to recognize the MHC + peptide it will get a positive signal → continues to live
- Negative selection: T-cells with a positive signal encounter different cells
- If the binding is too strong, the cell is eliminated
- If the binding is moderate, the cell continues living
Diversity in the B- and T-cell repertoire
T-cells and B-cells are very diverse:
- B-cells
- More D-segments
- Rarely have D-segments read in 3 frames
- More junctional diversity
- Total diversity: 5 x 1013
- T-cells
- More V-segments
- Often have D-segments read in 3 frames
- More J-segments
- More V-gene pairs
- Total diversity: 1018
It may seem as if T-cells are much more diverse than B-cells, but this is not completely true. When B-cells are developed, are in secondary lymphoid organs and encounter an antigen, they have the capacity to change again → in the germinal centers, extra mutations are introduced in the V-regions to introduce extra affinity for antigens.
This is important while distinguishing immune responses → when exposed to a vaccine twice, the response will be much stronger and faster the second time.
Join with a free account for more service, or become a member for full access to exclusives and extra support of WorldSupporter >>
Mechanisms of Disease 1 2020/2021 UL
- Mechanisms of Disease 1 HC1: Introduction to G2MD1
- Mechanisms of Disease 1 HC2: Introduction to the immune system
- Mechanisms of Disease 1 HC3: Innate and adaptive immune responses & key cytokines
- Mechanisms of Disease 1 HC4: Pathology of normal immune response
- Mechanisms of Disease 1 HC5: B- and T-cell generation and diversity
- Mechanisms of Disease 1 HC6: Mechanisms of adaptive immunity
- Mechanisms of Disease 1 HC7: Effector mechanisms of antibodies
- Mechanisms of Disease 1 HC8: B-cell development and antibodies
- Mechanisms of Disease 1 HC9: Tissue injury and repair
- Mechanisms of Disease 1 HC10: Repair mechanism
- Mechanisms of Disease 1 HC11: Pathology of inflammatory reactions
- Mechanisms of Disease 1 HC12: Introduction to infectious diseases
- Mechanisms of Disease 1 HC13: Bacteria
- Mechanisms of Disease 1 HC14: Viruses
- Mechanisms of Disease 1 HC15: Fungi and parasites
- Mechanisms of Disease 1 HC16: Invaders
- Mechanisms of Disease 1 HC17: Host versus invader
- Mechanisms of Disease 1 HC18: Immune deficiencies and infection risk
- Mechanisms of Disease 1 HC19: Pathology of infectious diseases
- Mechanisms of Disease 1 HC20: Diagnostics of infectious diseases
- Mechanisms of Disease 1 HC21: Essential microorganisms
- Mechanisms of Disease 1 HC extra: Mycobacterial infections (tuberculosis)
- Mechanisms of Disease 1 HC22: Antimicrobial therapy
- Mechanisms of Disease 1 HC23: Principles of antibiotic pharmacotherapy
- Mechanisms of Disease 1 HC24: Introduction MOOC
- Mechanisms of Disease 1 HC25: Epidemiology
- Mechanisms of Disease 1 HC26: Prevention and control
- Mechanisms of Disease 1 HC extra: COVID-19
- Mechanisms of Disease 1 HC27: Mechanisms of hypersensitivity reactions
- Mechanisms of disease 1 HC28: Pathology of allergy
- Mechanisms of Disease 1 HC29: Asthma
- Mechanisms of Disease 1 HC30: Pathology of autoimmunity
- Mechanisms of Disease 1 HC31: HLA and autoimmunity
- Mechanisms of Disease 1 HC32: Vasculitis
- Mechanisms of Disease 1 HC33: Systemic Lupus Erythematosus
- Mechanisms of Disease 1 HC35: Infections and autoimmunity
- Mechanisms of Disease 1 HC36: Immune cells in rheumatoid arthritis
- Mechanisms of Disease 1 HC37+38: Pharmacology: immunosuppression
- Mechanisms of Disease 1 HC39: Pathology of transplantation
Contributions: posts
Spotlight: topics
Mechanisms of Disease 1 2020/2021 UL
Deze bundel bevat aantekeningen van alle hoorcolleges van het blok Mechanisms of Disease 1 van de studie Geneeskunde aan de Universiteit Leiden, collegejaar 2020/2021.
This bundle contains notes of all lectures from the module Mechanisms of Disease 1, Medicine, Leiden
...Online access to all summaries, study notes en practice exams
- Check out: Register with JoHo WorldSupporter: starting page (EN)
- Check out: Aanmelden bij JoHo WorldSupporter - startpagina (NL)
How and why use WorldSupporter.org for your summaries and study assistance?
- For free use of many of the summaries and study aids provided or collected by your fellow students.
- For free use of many of the lecture and study group notes, exam questions and practice questions.
- For use of all exclusive summaries and study assistance for those who are member with JoHo WorldSupporter with online access
- For compiling your own materials and contributions with relevant study help
- For sharing and finding relevant and interesting summaries, documents, notes, blogs, tips, videos, discussions, activities, recipes, side jobs and more.
Using and finding summaries, notes and practice exams on JoHo WorldSupporter
There are several ways to navigate the large amount of summaries, study notes en practice exams on JoHo WorldSupporter.
- Use the summaries home pages for your study or field of study
- Use the check and search pages for summaries and study aids by field of study, subject or faculty
- Use and follow your (study) organization
- by using your own student organization as a starting point, and continuing to follow it, easily discover which study materials are relevant to you
- this option is only available through partner organizations
- Check or follow authors or other WorldSupporters
- Use the menu above each page to go to the main theme pages for summaries
- Theme pages can be found for international studies as well as Dutch studies
Do you want to share your summaries with JoHo WorldSupporter and its visitors?
- Check out: Why and how to add a WorldSupporter contributions
- JoHo members: JoHo WorldSupporter members can share content directly and have access to all content: Join JoHo and become a JoHo member
- Non-members: When you are not a member you do not have full access, but if you want to share your own content with others you can fill out the contact form
Quicklinks to fields of study for summaries and study assistance
Main summaries home pages:
- Business organization and economics - Communication and marketing -International relations and international organizations - IT, logistics and technology - Law and administration - Leisure, sports and tourism - Medicine and healthcare - Pedagogy and educational science - Psychology and behavioral sciences - Society, culture and arts - Statistics and research
- Summaries: the best textbooks summarized per field of study
- Summaries: the best scientific articles summarized per field of study
- Summaries: the best definitions, descriptions and lists of terms per field of study
- Exams: home page for exams, exam tips and study tips
Main study fields:
Business organization and economics, Communication & Marketing, Education & Pedagogic Sciences, International Relations and Politics, IT and Technology, Law & Administration, Medicine & Health Care, Nature & Environmental Sciences, Psychology and behavioral sciences, Science and academic Research, Society & Culture, Tourisme & Sports
Main study fields NL:
- Studies: Bedrijfskunde en economie, communicatie en marketing, geneeskunde en gezondheidszorg, internationale studies en betrekkingen, IT, Logistiek en technologie, maatschappij, cultuur en sociale studies, pedagogiek en onderwijskunde, rechten en bestuurskunde, statistiek, onderzoeksmethoden en SPSS
- Studie instellingen: Maatschappij: ISW in Utrecht - Pedagogiek: Groningen, Leiden , Utrecht - Psychologie: Amsterdam, Leiden, Nijmegen, Twente, Utrecht - Recht: Arresten en jurisprudentie, Groningen, Leiden
JoHo can really use your help! Check out the various student jobs here that match your studies, improve your competencies, strengthen your CV and contribute to a more tolerant world
1690 |
Add new contribution