Download Free Medical Models of Autoimmune Diseases PowerPoint Presentation

Models of Autoimmune Diseases PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : "Models of Autoimmune Diseases" is an illuminating PowerPoint (PPT) presentation exploring various experimental models used to study autoimmune disorders. Through detailed analysis, it elucidates the mechanisms underlying immune dysregulation, genetic predispositions, and environmental triggers. This comprehensive overview serves as a valuable resource for researchers and clinicians in understanding and treating autoimmune conditions.

Tags : autoimmune diseases,immune thrombocytopenia,models of autoimmune diseases,animal models for autoimmune diseases,three types of autoimmune diseases,diseases

Published on : Mar 09, 2024 | Views : 1094 | Downloads : 0

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Models of autoimmune disease r.boyton@imperial.ac.uk
Slide 2-

Autoimmunity In this lecture you will learn: What is an autoimmune disease Examples of autoimmune models Pathogenic mechanisms and regulation (Tregs) in autoimmune disease The search for genes underlying autoimmunity - associations with HLA alleles and other markers The search for the target antigens in autoimmunity Microarray studies The need for good experimental models of autoimmune diseases - Non-obese diabetic (NOD) mouse model New models from transgenic and knockout mice Experimental allergic encephalomyelitis (EAE) model
Slide 3-

What is an autoimmune disease? Autoimmune diseases are those caused by specific immunological attack of antigens expressed by self tissues They should, therefore, by definition, show some amelioration with immunosuppressive/anti-inflammatory therapies.
Slide 4-

Some examples Classic, textbook, autoimmune diseases defined by clinical tests of autoreactivity: systemic lupus erythamatosis (SLE) thyroiditis (Grave’s Disease, Hashimoto’s) myasthenia gravis Goodpasture’s disease Diseases of presumed autoimmune aetiology multiple sclerosis type I diabetes Crohn’s disease
Slide 5-

What do we know about where autoimmune disease come from The immune system normally works by selecting for antibody and T cell receptors that are useful for recognising foreign antigens, deleting those that recognise self So autoimmune disease must represent example where this process of self-tolerance has been by-passed or overcome in some way. Bear in mind that not all self-tolerance involves deletion of the self-reactive cells - they may be merely anergic i.e in an non-activatable state.
Slide 6-

Reasons for wanting human disease models Understand pathophysiology Understand interplay between different systems -can manipulate models Ethical issues Resource issues Rare diseases - collecting enough patients Complex diseases with genetic and environmental elements (resource issue)
Slide 7-

In vitro research models Pros simple inexpensive answers to Q on molecular/cellular interactions immortalised cells ethical (NB patient-derived cells/tissues) Cons Simple – cannot study systemic interactions growing cells phenotype changes Hayflick number Need a priori assumptions about disease process
Slide 8-

In vivo research models Pros complex answers to Q on physiology of organs systems / interventions KO / Tg animals Cons complex expense choice of species ethical (for some animals) legislation
Slide 9-

Choice of species - mice/rats Pros mammalian vertebrates very well characterised inbred strains -reliable, consistent, reproducible genetic modification is relatively easy many similarities, esp immunology inexpensive ethical issues Enormous range of reagents available (cytokines, antibodies) Cons inbred strains essentially naive, immunologically many differences ethical issues
Slide 10-

Move towards large animal models in medicine Pigs - cardiovascular research Primates - transplantation research HIV prime motivation - seen as more representative of humans Bring their own problems
Slide 11-

Pathogenic mechanisms in autoimmunity The key initiating event in an autoimmune response is the recognition of a peptide from self tissue, bound to an MHC molecule and then presented to an autoreactive T cell which becomes activated. However, the tissue damage may ultimately be caused by various mechanisms: Autoantibody e.g. myasthenia gravis (acetylcholine receptor), Goodpasture disease (type IV collagen of renal basement membrane), thyroiditis, systemic lupus erythamatosus Cellular inflammation e.g. CD4 and CD8 T cells, macrophages (type I diabetes, multiple sclerosis).
Slide 12-

An immunologists window onto the diabetes problem An antigen presenting cell presents a beta cell antigen on its MHC molecules This complex is recognised by an autoimmune T cell The T cell becomes activated CD4 T cell antigen presenting cell
Slide 13-

ppt slide no 13 content not found
Slide 14-

Spontaneous and induced animal models of human autoimmune disease Animal model Human Disease Non-obese diabetic mouse (NOD) Type I diabetes (also sialitis, thyroiditis, EAE) Bio-breeding (BB) rat Type I diabetes MRL mouse SLE BXSB mouse SLE (NZBxNZW)f1 mouse SLE NZB mouse Autoimmune haemolytic anaemia Experimental allergic encephalomyelitis - Multiple sclerosis Several bred mouse strains - SJL, B10.PL, PL/J - also Lewis rats, guinea pigs, chimpanzees Experimental allergic myasthenia gravis (EAMG) - various inbred mouse strains Myasthenia gravis Experimental allergic neuritis - Lewis rat, Balb/c mouse Guillain-Barre syndrome
Slide 15-

Spontaneous and induced animal models of human autoimmune disease 2 Animal model Human Disease Collagen induced arthritis - DBA/1 mouse Rheumatoid arthritis Pristane arthritis - DBA/1, CBA mouse Rheumatoid arthritis Proteoglycan arthritis - DBA/1 mouse Rheumatoid arthritis Adjuvant arthritis - Lewis rat Rheumatoid arthritis Streptococcal cell wall arthritis - Lewis rat Rheumatoid arthritis Experimental allergic uveitis - Lewis rat Uveitis Experimental allergic glomerulonephritis - Wistar-Kyoto rat, SJL mouse Goodpasture disease
Slide 16-

Which genes? • HLA genes - susceptibility and protection • Other genes - genome scans – Which target antigens? • epitope spread – Which mechanisms? • T cell subpopulations • Th1/Th2 cytokines Regulatory mechanisms Development of rational therapies based on this knowledge
Slide 17-

Many individuals can be shown to carry autoimmune T cells, yet most of the diseases are actually rather rare. So, in trying to deduce why clinical disease sometimes develops, we need to consider: failure to regulate the immune response properly contributory role of multiple predisposing genes role of infectious disease (of course, these may all be inter-linked)
Slide 18-

T cell maturation, differentiation and repertoire selection occurs mainly in the thymus Tolerance to self tissues depends on central tolerance - deleting those cells found during differentiation in the thymus to be self reactive - and on peripheral tolerance - regulating any self-reactive cells that have entered the immune repertoire.
Slide 19-

If negative selection of self-reactive T cells depends on engagement self antigens during passage through the thymus, how could this work for proteins specifically expressed at other sites? Answer came through the studyt of Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy(APECED), A rare human autoimmune disorder that is inherited in an autosomal recessive manner and is characterized by various endocrine deficiencies, chronic mucocutaneous candidiasis and ectodermal dystrophies
Slide 20-

Mutations in the autoimmune regulator (AIRE) protein are the causative factor in development of the APECED. In mice, the absence of the analogous protein aire influences ectopic expression of peripheral tissue antigens in thymic medullary epithelial cells (MECs), resulting in the development of an autoimmune disorder similar to APECED
Slide 21-

AIRE - ‘autoimmune regulator’ - a gene controlling transcription of self antigens in the thymus
Slide 22-

Some immune system molecules must be involved in the physiological control of immune responses, including those against self, as knockout mice show extreme autoimmune phenotypes CTLA-4 knockouts - fatal (around 3 weeks) autoimmune lymphoproliferative disease FoxP3 knockouts (or Scurfy) - as above TGFb knockouts - wasting syndrome, multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death Cbl-b knockouts - auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs, and parenchymal damage
Slide 23-

Natural CD4+CD25+FoxP3+ Tregs arise in the thymus through homeostatic processes. Natural Tregs curb autoreactive T cells by subduing their function, without killing them.There is a natural FoxP3 mutant mouse, ‘Scurfy’This mouse and the engineered FoxP3 mutants have the same phenotype: spontaneous, multi-organ autoimmunity and wasting disease. REGULATORY T cells (Tregs) have a role in peripheral tolerance
Slide 24-

Identifying and correcting defects in CD4+ CD25 + regulatory cell in NOD diabetes Reduced number of Tregs in the periphery Reduced function of Tregs Small numbers of expanded Tregs transferred to NODS reverse even ongoing disease
Slide 25-

The non-obese diabetic (NOD) mouse model of diabetes NOD are a strain of laboratory mice that spontaneously develop type I diabetes They are considered one of the best animal models of a human autoimmune disease The genetics and immunology of the disease process are relatively similar in humans and NOD mice
Slide 26-

Which beta cell peptides could be targeted by autoimmune T cells? In order to study and manipulate T cells that cause diabetes, it is helpful to know which antigens they recognize Some candidates: Glutamic acid decarboxylase 65 (GAD65) Insulin Heat shock protein 60 IA-2 phosphatase
Slide 27-

Searching for autoantigens in a model autoimmune disease Which proteins/peptides can induce the disease following injection in adjuvant? Which peptides from proteins of the target tissue cause activation of T cells from the mouse? Which clones from an organ specific expression library stimulate autoimmune T cells? Grow clones against different peptides and see which can transfer disease (Koch’s postulates) Tolerise with the peptide of choice and see if the disease is ameliorates Over-express the antigen transgenically, as a self-antigen in the thymus and see of disease is turned off.
Slide 28-

How many epitopes within the target tissue are recognized by T cells during autoimmune attack?- how to find them?
Slide 29-

T cell responses to myelin In the CNS, oligodendrocytes ensheath axons in myelin During the course of MS and EAE, T cell responses may be observed to peptides from myelin proteins including myelin basic protein (MBP), proteoliporotein (PLP), myelin oligodendrocyte glycoprotein (MOG).
Slide 30-

Epitope spread? Hypothesis to explain a relapsing and remitting disease: T cells initially recognize a single peptide epitope from the myelin sheath; this leads to myelin destruction, exposure of more protein epitopes and thus the next wave of specific pathogenic T cells Evidence for epitope spread:Paul Lehmann and Eli Sercarz. Nature ’92. SJL mice were immunised with guinea pig MBP. T cell responses were analysed on Day 9 and 40. Initially T cell response was only to the immunodominant MBPAc 1-11 epitope. On Day 40 T cell responses to MBP Ac1-11, MBP 35-47, MBP 81-100 and MBP 121-140 were found
Slide 31-

A detailed understanding of TCR/peptide/MHC interactions in autoimmunity should facilitate the design of effective immunotherapies Antagonist peptides are potent disease inhibitors in murine models, but few successful human trials so far…..
Slide 32-

Which are the autoimmune predisposing genes?How many are there?
Slide 33-

A disease backcross to identify candidate disease loci - 1 Autoimmune diseases are polygenic, susceptibility being conferred by subtle variations in multiple, normal genes that, in an appropriate environment, add up to an overall phenotype leading to autoimmune disease Thus, for many of these diseases, the combined effect of particular disease associated alleles at, perhaps, 5-15 different loci, may give the disease phenotype Most of the loci have not been identified as specific genes. Candidates are MHC genes, cytokine and cytokine receptor genes, and genes encoding proteins in the target tissues.
Slide 34-

A disease backcross to identify candidate disease loci - 2 Identify a susceptible and a resistant strain. Cross them - the F1 generation is generally resistant. In the next generation (back-crossing to parental susceptible strain) there will be segregation of the resistant and susceptible phenotype. It is assumed that susceptibility is associated by areas of homozygosity for disease genes So mapping with polymorphic markers distributed across the genome to find these areas of homozygosity will lead to positions for the disease genes. Can use microsatellite markers - size polymophisms (eg variable number CA repeats) Very successful approach - many quantitative trait loci (QTL) for autoimmune diseases are registered in the mouse genome database.
Slide 35-

ppt slide no 35 content not found
Slide 36-

Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA
Slide 37-

RA-like pathology in SKG spontaneous mutant mice a–e, Swelling of joints: fingers (a) and toes (b) of a 4-month-old SKG mouse; forepaw (c) and hindpaw (d) of a 6-month-old SKG mouse; deformity of bilateral ankles and swelling of the base of the tail (e) in an 18-month-old SKG mouse. f–i, X-ray photographs of joints: wrist (f) and ankle (h) of an 8-month-old SKG mouse, and wrist (g) and ankle (i) of an 8-month-old BALB/c mouse. j, Time course of joint swelling in female SKG mice, and arthritis scores of 8-month-old female (F) and male (M) SKG mice (n = 15 each). Vertical bars represent s.e.m. See Methods for details on the scoring of joint swelling. k–p, Histology of arthritis and extra-articular lesions in SKG mice
Slide 38-

Autoimmune arthritis in SKG mice is highly dependent on the development of CD4+ T cells secreting IL-17, a proinflammatory cytokine capable of recruiting and activating neutrophils and other inflammatory cells
Slide 39-

Further reading Mathis D and Benoist, C. A decade of AIRE. Nat. Rev. Immunol. 7, 645 Zheng, Y and Rudensky, A. FoxP3 in the control of the regulatory T cell lineage. Nat. Immunol. 8, 457 Gold, R et a. Understanding pathogenesis and therpay of multiple sclerosis via animal models. Brain 129, 1953.