Part IB: List of Lecture synopses
Synopses Of Lectures - MVST Part IB Pathology (Biology of Disease) and NST Part IB Pathology
Michaelmas 2011
- Disease and the eradication of disease: Professor G L Smith
Pathology is the study of disease. This course aims to understand the following questions: what causes disease, what are the mechanisms that underpin disease processes, and how can disease be prevented or treated? It will consider different diseases, including those caused by infectious agents, (such as bacteria, fungi, viruses and parasites), or by uncontrolled cell division leading to cancer, or by malfunction of the immune system leading to autoimmune disease or excessive inflammation leading to arthritis. This lecture will provide examples of how disease can be controlled or eradicated with emphasis on prevention by vaccination. There are vaccines that prevent several bacterial and viral diseases and also some cancers. But the greatest success story so far is the global eradication of smallpox. Smallpox remains the only human infectious disease to be eradicated, but why is this and why has vaccination failed to control other diseases such as AIDS, tuberculosis and malaria? - Innate immunity: Professor A Moffett The immune system is generally divided into two systems: innate and adaptive. Most potential infections are dealt with by physical and chemical barriers, and the innate immune system is initiated if these are breached. A first step in innate immunity is recognition of infection by detection of pathogen-associated molecular patterns (PAMPs). There are a number of different proteins dedicated to this task, the most well known being the Toll-like receptors. The next step is recruitment of cells, such as neutrophils, macrophages and natural killer cells, as well as soluble factors, including the complement system, which is covered in detail in lecture 4, Defensins, Cytokines and Interferon to the site of damage.
- Inflammation: Professor A Moffett
If pathogens penetrate the epithelial inflammation is induced at the site of infection. This is a coordinated response to infection or injury that results in a battery of effector mechanisms to eliminate the infection. Increased vascular permeability allows fluid, proteins and inflammatory cells to infected tissues. Other systems that come into play include: chemokines to regulate lymphocyte traffic, plasma enzymes for clotting, cytokines that affect cellular behaviour and complement. The acute inflammatory response generally resolves as the tissue heals. Failure to resolve the problem, such as the persistence of an intracellular pathogen, can result in a granuloma, where the remaining infected tissue is contained. - Complement: Professor A Moffett
The complement system is a major arm of innate immunity. It comprises about 30 proteins, the main ones being C1-C9, made in the liver. Infection triggers a cascade of proteolytic cleavage reactions that result in coating of the surface of microbes to aid phagocytosis, perforation of microbial membranes by the membrane attack complex (MAC) and recruitment of inflammatory cells. There are three main ways of activating complement, all of which result in cleavage of C3, which then tags bacterial surfaces. Host cells make regulatory proteins such as Decay Accelerating Factor and Membrane Co-factor Protein, that protect them from complement activation. Other small peptides released during complement activation include anaphylatoxins, which induce local inflammation. - The Adaptive Immune System: Dr A P Kelly
The theoretical basis for an adaptive immune system requires the possession of a large repertoire of clonally variable receptors. This requirement is met by lymphocytes. The acquisition of clonally variable receptors underpins the characteristics of the adaptive immune response, which distinguish it from innate immunity, namely specificity and memory. In fact the vertebrate immune system has developed two complementary but distinct antigen-specific receptor repertoires, expressed by the B and T lymphocytes respectively. The essential characteristics of each will be emphasised – native recognition by B cells, processed antigen by T cells. The organisation of lymphoid tissue will be discussed and the recirculation properties of lymphocytes – encapsulated by the phrase “patrol and respond” – will be introduced. - B Cells and Antibodies: Dr A P Kelly
The protein structure of antibody molecules will be covered from four aspects; the division of the molecules into antigen binding (variable) and effector function-linking (constant) regions; the formulation of the antigen-combining site by the folding of polypeptide chains – the heavy and light chains; the mobility within the protein and its significance in the formation of antibody-antigen complexes; the existence of membrane bound and soluble forms of protein. The different classes and subclasses of antibody will be introduced with a brief review of their properties. The principle of somatic diversity of immunoglobulin molecules will be stressed. The functions of antibody and their role in recruiting immune effector mechanisms via Fc receptors and complement will be discussed. The concepts of avidity and affinity will be defined. - The Major Histocompatibility Complex: Dr A P Kelly
The protein structure of MHC molecules will be described and the properties of MHC molecules in binding peptides illustrated. The nomenclature of MHC molecules will be explained, including the existence of distinct classes and the co-dominant nature of expression. The genetic polymorphism of MHC molecules will be discussed in outline and the functional consequences of this explained in terms of peptide binding. The cell biology of class I and class II molecules and their roles in presenting antigen from different sources will be discussed. - T Cells: Dr A P Kelly
An outline of the development of T cells with emphasis on the outcome in terms of repertoire selection, tolerance and the generation of distinct classes of T cells which recognise the distinct classes of MHC (CD4 and CD8 T cells). The differentiation of function between CD4 and CD8 T cells will be presented in simplified form. T cell receptor will be introduced and the mechanism of repertoire generation examined. The role of T cells in regulating antibody responses and the cellular interactions of dendritic cells, T cells and B cells will be discussed. The concepts of co-stimulation, class switching and affinity maturation will be explained. - Tolerance: Professor J Trowsdale
A range of processes is in place to avoid recognition and damage of self tissues, a concept referred to as tolerance. Mechanisms of tolerance are generally divided into central and peripheral. Central tolerance of T cells takes place in the thymus and in the bone marrow for B cells. Mechanisms for peripheral tolerance have been characterised as anergy, ignorance and suppression. Recently the profound role of regulatory T cells has become to be appreciated. The self, non-self models of Medawar and Burnet will be compared to Matzinger’s “Danger Hypothesis”. The experimental manipulation of tolerance will be discussed, with one or two examples. - Autoimmunity: Professor J Trowsdale
Although the immune system has an elaborate system of checks and balances to ensure self tolerance, occasionally this system breaks down. When the immune system attacks host components causing pathological change, this is called autoimmunity. Many people experience an autoimmune reaction during their lifetime. Mostly these are short-lived, self-resolving sequelae of infection. However in some 5% of individuals the reaction is chronic, debilitating and even life-threatening. It is these latter conditions where serious immunopathology occurs, usually considered as autoimmune disease. Autoimmunity results from the breakdown of self-tolerance. Autoimmune disease should be seen as a spectrum encompassing single-antigen organ-specific conditions at one extreme to systemic polyspecific diseases at the other. The profound influences of genetics and environmental factors will be explored. Clinical examples will be used to illustrate the underlying causes of autoimmunity. Different explanations for the initiation of autoimmune disease will be compared. The role of experimental models of autoimmune disease in elucidating the underlying causes and mechanisms will be discussed. - Hypersensitivity: Professor J Trowsdale
Hypersensitivity refers to immune responses that are damaging rather than helpful to the host. In other words these are over-reactions of the immune system. Gell and Coombs proposed a classification scheme that defined four types of hypersensitivity reactions. The first 3 are mediated by antibody, the 4th by T cells. The four types of hypersensitivity will be outlined. Type 1 hypersensitivity will be familiar to the majority of students as allergy. The role of IgE and mast cells will be briefly outlined. This will be compared to type II hypersesitivity, which involves IgM or IgG. Blood transfusion is the oldest form of transplantation and is an example of type II hypersensitivity. Both ABO and Rhesus blood group systems will be covered. Type III IgG hypersensitivity reactions occur when the antigen is soluble and in high quantities, in contrast to low levels which tend to produce IgE responses. Immune complexes form and are deposited in tissues. Finally, type IV or Delayed type hypersensitivity (DTH) is mediated by specific T cells, that release cytokines, which in turn recruit mononuclear cells. The effect is usually maximal in 48-72 hours. - Transplantation: Professor J Trowsdale
Transplantation is the introduction of biological material - organs, tissue, cells, fluids - into an organism. The problem with transplanting tissue is that most cells express polymorphic surface antigens encoded by the MHC. Variation between the donor and recipient at the MHC results in rejection. Even if there is a perfect match other ‘minor’ antigens can be recognised by the immune system. Unlike ABO blood typing there are no universal donors. If tissue is mis-matched it is generally rejected. This topic illustrates self non-self discrimination and the importance of inflammation as a trigger of immune responses. Discrimination of the two pathways, direct and indirect, of cellular transplant rejection, provides reinforcement of the concepts of antigen presentation. Different transplant situations will be discussed in relation to the need for donor/recipient matching and immunosuppression. - Nature of Viruses: Professor A C Minson
Viruses are submicroscopic intracellular parasites. At their simplest they consist of a nucleic acid genome surrounded by a protective shell composed of repeating protein subunits, but some viruses acquire an outer membrane as they leave the cell and are therefore chemically more complex. The great diversity of viruses results from the different symmetrical arrangements of the protein subunits in the shell, the different types of nucleic acid that comprise the genome and the wide range of sizes, or coding potential, of the genome. These are the key features used to describe and classify viruses. Despite the great variation in the structure and chemistry of virus particles, the life style of all animal viruses is fundamentally similar. A virus must attach to the surface of a host cell via specific receptors, and must penetrate the plasma membrane to deliver its genome to the cell machinery. The genome must be copied to provide progeny genomes, and translated into proteins to provide new protein shells. Association of new protein shells with progeny genomes completes the cycle. The purpose of the lecture is to describe the diversity of viruses and to illustrate the unifying features. - Viral Multiplication in the Host Cell: Professor A C Minson
Once inside the cell the virus is, in essence, a set of parasitic genes whose purpose is to subvert the cell’s synthetic machinery:- to convert the cell to a virus production factory. This lecture focuses on how this subversion is achieved and how the cell responds. Events in the infected cell depend on the type of nucleic acid comprising the virus genome. Most DNA viruses use host transcription machinery to synthesise virus specific messenger RNA, whereas RNA viruses require no such function. Most DNA viruses therefore require host nuclear functions and subvert the transcription process, while most RNA viruses replicate independently of the nucleus and subvert translation. DNA viruses require high levels of deoxyribonucleotides for genome replication and often induce the resting cell into cell cycle in order to increase dNTP pool sizes. The cell responds to infection by producing interferon, a cytokine which can inhibit protein synthesis in infected cells, and in some cases by apoptosis. The consequences of infection thus range from proliferation to cell death. - Responses to Viral Infection: Professor A C Minson
Infection involves gaining access to susceptible cells and tissues (a portal of entry), multiplication to high levels (at an amplification site), and a means of transmission to new hosts (portal of exit). Superficial infections use the same tissue for entry, amplification and exit, whereas systemic spread results in the infection of a wider range of tissues, more complex pathological outcomes, and a variety of possible exit routes. The host responds to infection using innate (interferon, complement, natural killer cells) and acquired immunity (humoral and cell mediated). Viruses have evolved a variety of mechanisms to evade these defences. The importance of different components of the defence system varies depending on the virus. An understanding of the important responses to a particular infection, and of the evasion strategies of the virus concerned, are important in vaccine or immune therapy design. - Acute and Chronic Infection: Professor A C Minson
Most viruses are eliminated by host responses. These viruses cause acute infections and are under constant pressure to find new hosts if they are to survive. Some viruses are not eliminated, but persist in the host as chronic infections or latent (silent) infections which reactivate from time to time. This lecture will examine the different strategies of viruses which cause acute or persistent infections and the implications of these strategies for transmission and survival of the virus in host populations. The pathological consequences of infection depend on interactions between the virus and the host. Acute infections often cause direct tissue damage and acute inflammation. Persistent viruses survive in the host in the face of an immune response which controls the virus, but fails to clear it. In the long term, chronic immunopathological damage may result. - Epidemiology of Viral Infection: Professor A C Minson
The epidemiological characteristics of a particular virus can be guessed from a knowledge of its exit portals and transmission routes (e.g. Respiratory aerosol, sexual, faeco-oral), More commonly our knowledge of transmission is poor and insights are gained by determining the prevalence of the virus in the community and the major risk groups for infection. Surveillance of the population is achieved by direct isolation or detection of virus, or more commonly by using serological surveys to obtain evidence of past infection: who has been infected, and in which age group, social group, behavioural group or racial group is infection most common? Similar principles apply to surveillance of animal populations. Monitoring disease incidence is also important and can be achieved on a very large scale through national networks of medical or veterinary practitioners, but disease incidence is not necessarily a measure of infection incidence. Many viruses are very prevalent in the host population but cause disease in only a minority of infected individuals (e.g. the very young, the very old, the immune-suppressed, the foetus). - Combating Viral Infection: Professor A C Minson
Like other infectious diseases, virus infection can be combatted in three ways: by preventing transmission; by drug therapy; or by vaccination. The implementation of public health measures (e.g. clean water supplies, vector control) for human diseases or quarantine/slaughter policies for animal diseases are highly effective, but at least for human infections, are difficult or impossible for viruses spread by aerosol or contact routes. The development of antiviral drugs has seen substantial advances during the last decade and is likely to have significant impact on the treatment of chronic or recurrent infections, but specific treatment of acute infections requires rapid diagnosis. Vaccination remains the most effective method of combating or eliminating virus infections. The lecture will describe the impact of immunological and molecular knowledge on vaccine design and consider the alternative aims of vaccination strategies: the protection of the ‘at risk’ individual from infection or the interruption of transmission through ‘herd immunity’ - Prion Diseases: Professor A C Minson
Transmissible spongiform encephalopathies (TSEs) are progressive neurodegenerative diseases of the CNS which are naturally or experimentally transmitted. Because of the submicroscopic size of the infectious particle and the very long incubation period exhibited by these diseases (years or decades) they were originally described as ‘slow virus diseases’, but they are almost certainly not caused by viruses but by aberrant forms of host protein molecules termed ‘prions’. The lecture will describe the key features of the sporadic, inherited and naturally transmitted forms of TSE, the development of the prion theory, and the implications for clinical and agricultural practice. The current status of the BSE and variant CJD epidemics will be reviewed. - Introduction to Parasitic Diseases: Dr I B Kingston
This is the first of three lectures concerned with eukaryote organisms that have an endo-parasitic form of life and cause diseases of major public health and veterinary concern. The scale of the public health problem caused by parasitic diseases is discussed and major groups of protozoan and metazoan parasites that cause disease are outlined. These include protozoan parasites that cause leishmaniasis, sleeping sickness, babesiosis, malaria and toxoplasmosis. The metazoan parasites are worms (or helminths) mainly belonging to two separate phyla, Nematoda, that include many gastrointestinal and tissue dwelling worms, and the platyhelminthes, that include cestodes (tapeworms) and trematodes (flukes). The diversity of parasite life cycles and their modes of transmission are illustrated, including examples of direct and indirect life cycles with different routes of infection. The role of parasite behaviour and vector organisms in facilitating transmission of parasites from one host to another is outlined. - Key Examples of Parasitic Diseases: Malaria: Dr I B Kingston
In this and the following lecture, two parasitic diseases, one caused by protozoan parasites and one caused by parasitic helminths will be considered. These two infections illustrate why many parasitic infections are serious and a continuing public health problem.
Malaria
The impact of malaria caused by protozoan parasites of the genus Plasmodium on world health, and the life-cycle of malaria parasites in their human and mosquito hosts. Natural innate resistance and acquired immunity to malaria in human populations living in endemic areas. Morbidity caused by malaria, pathological symptoms, and cerebral malaria caused by Plasmodium falciparum. - Key Examples of Parasitic Diseases: Schistosomiasis: Dr I B Kingston
The distribution of infections with parasitic trematode worms of the genus Schistosoma and their association with water in tropical and sub-tropical regions. The biology and life-cycle of schistosomes in their human and freshwater snail hosts. Anti-schistosome immune responses and how schistosomes manage to chronically infect their human hosts, despite living in the host blood stream apparently exposed to host immune effector mechanisms. The problem of continuing susceptibility of children to reinfection after chemotherapeutic cure. Morbidity associated with schistosomiasis and the influence of anti-parasite immune responses in the development of liver fibrosis and severe hepatosplenic disease caused by Schistosoma mansoni and S. japonicum infections. - Characteristics of Fungi: Dr A Carmichael
The characteristics of fungi in general. Host defences against fungi. Anti-fungal drugs. The patterns of fungal infections, including commensals, superficial infections and systemic (deep) infections. - Systemic fungal infections: Dr A Carmichael
The distinctions between systemic pathogens and systemic opportunists, with examples of the spectrum of serious fungal infections including environmental dimorphic fungi, Candida albicans, Pneumocystis and Aspergillus.