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Part IB List of Lecture Synopses

Synopses Of Lectures - MVST & NST Part IB Pathology (Biology of Disease)

Michaelmas 2018

1-4.      The Immune Response to Cell Injury and Infection: Dr A Kelly

Cell injury is the starting point for most disease processes.  The nature of injury will be discussed together with the cellular response and final outcome, recovery, necrosis or apoptosis. A major cause of cell injury is infection. The role of the innate and adaptive immune systems in protecting the host from infection will be introduced. The importance of barriers, phagocytes, NK cells and complement in control of infection will be outlined. Particular emphasis will be placed on the role of the complement cascade. Recognition is a key feature of the immune system. How the immune system senses the presence of pathogens and damage and how the acute inflammatory response is initiated and coordinated will be covered.  This includes the sequential events that allow leukocytes to emigrate from the circulation into the site of injury together with the beneficial and harmful effects of the exudate. The pivotal role of the macrophage in orchestrating the initial inflammatory response and subsequent healing process will be explained.  Finally, how the innate system directs the subsequent adaptive response to be appropriate for the nature of the infecting organism will be introduced.


5.         The Adaptive Immune System:  Dr A 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.


6.         B Cells and Antibodies:  Dr A 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.

 7.         The Major Histocompatibility Complex Dr A 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.


8.         T Cells:  Dr A 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. 


9.         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.


10.       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.


11.       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 hypersensitivity, 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.


12.       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.


13.       The nature of viruses:  Professor G L Smith

Viruses are very small, numerous, intracellular parasites. The simplest viruses consist of a nucleic acid genome surrounded by a protective shell of repeating protein subunits, but some viruses acquire an outer membrane as they leave the cell and are chemically more complex. The great diversity of viruses results from the different arrangements of the protein subunits in the protective shell, the different types of nucleic acid that comprise the genome and the wide variety of coding potential of the genome. These features are used to describe and classify viruses. Despite the great variation in virus size and structure, the replication of viruses is fundamentally similar. A virus must attach to the surface of a susceptible host cell via specific receptors and penetrate the cell to deliver its genome into the cell. The virus genes are then expressed to produce new virus proteins that replicate the genome and provide protein subunits for the new virus particles. Association of protein shells with virus genomes produces new virus particles that exit the infected cell to complete the replication cycle. This lecture will describe the nature of viruses and illustrate features of their replication cycle.


14.       Consequence of viral infection:  Professor G L Smith

The lecture will start by illustrating how viruses with RNA or DNA genomes convert their genes into mRNA to produce new virus proteins and how the diverse range of virus genomes are replicated. Once inside a cell a virus is, in essence, a set of parasitic genes whose purpose is to subvert the cell’s synthetic machinery and convert the cell into a factory for production of new virus particles. We will consider how this subversion is achieved, how the cell responds and what changes virus infection can bring to cells.  DNA viruses require high levels of deoxyribonucleoside triphosphates (dNTPs) for genome replication and may induce the resting cell into cell cycle to produce these dNTP pool sizes. Although virus replication leading to cell death is one consequence of infection, there are other outcomes such as latent infection and cell transformation leading to cancer. The consequences of virus infection thus range from cell proliferation to cell death.



15.       Viruses in the multicellular host:  Professor G L Smith

In the multicellular host a virus is confronted with physical and immunological defences to prevent or restrict infection. To replicate and spread to other hosts a virus must gain access to susceptible cells and tissues (portal of entry), multiply to high levels (at an amplification site) and leave the host (portal of exit) in a manner that ensures transmission to new hosts. Cells sense virus infection via pattern recognition receptors (PRRs) that detect pathogen associated molecular patterns (PAMPs) and respond to infection by producing cytokines, chemokines and interferons and undergoing apoptosis. Interferon is a cytokine that inhibits indirectly virus protein synthesis and so prevents virus replication. The importance of different components of the immune system varies depending on the virus. Viruses have evolved many strategies to evade or inhibit the host innate and adaptive immune response to infection and an understanding of the important responses to a particular infection, and of the evasion strategies of the virus concerned, are important for design of vaccines or immune therapy.


16.       How viruses persist and are transmitted.  Professor G L Smith

Most viruses are eliminated by host responses. These viruses cause acute infection 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 or latent (silent) infections that reactivate from time to time. Superficial infections use the same site 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.  This lecture will examine the different strategies of viruses that cause acute or persistent infections and the implications of these strategies for the 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 at the site of infection. Persistent viruses survive

in the host in the face an immune response that controls the virus but fails to eliminate it. In the long term chronic immunopathological damage may result. The lecture will conclude with examples of the impact of virus infections in veterinary and human medicine.


17.       Influenza and hepatitis viruses:  Professor G L Smith

Influenza virus can cause repeated, acute respiratory infections that are highly seasonal. This virus is able to escape existing immunity by undergoing antigenic variation of its surface protein, the haemagglutinin (HA), by either antigenic drift or shift. Drift is the gradual accumulation of mutations that enable escape from neutralising antibodies, whereas shift is a complete change of the HA protein caused by re-assortment of virus RNA segments during coinfection with two influenza viruses.  This can lead to the emergence of viruses able to cause a pandemic. Three types of hepatitis virus (A, B and C) will be considered. Hepatitis A virus (HAV) is a small RNA virus transmitted by the faecal-oral route and that causes an acute jaundice. In contrast, hepatitis B virus (HBV) is a hepadnavirus and has a small, circular, partially dsDNA genome. Despite being a DNA virus, HBV replicates its genome via reverse transcription (like retroviruses). HBV infection can cause either acute or chronic infection with the latter predisposing to the development of liver cancer (hepatocellular carcinoma).  An effective genetically engineered vaccine against HBV has been used widely since 1986. Hepatitis C virus (HCV) is a flavivirus with an RNA genome and has huge variation and diversity. Like HBV, HCV can cause either acute or chronic infection with the latter inducing liver cancer. There is no vaccine for HCV, but anti-viral drugs have been developed that lead to a complete cure of the majority of infected patients.


18.       Prions, Zika virus and HIV: Professor G L Smith

This lecture will consider prions, the current Zika virus outbreak and human immunodeficiency virus (HIV). Prions are infectious proteins that cause slow neurological diseases in man and animals that are ultimately fatal and are called transmissible spongiform encephalopathies (TSEs).  These diseases include kuru in Papua New Guinae (caused by cannibalism),

Creutzsfeldt-Jakob disease (CJD), scrapie in sheep and bovine spongiform encephalopathy

(BSE) in cattle. The BSE epidemic in UK, led a decade later to an increased number of cases of CJD, called new variant (nvCJD), in humans, due to the consumption of BSE-infected food. Zika virus is a flavivirus, related to dengue virus, and is transmitted by mosquito bite. From 2015 it has caused a large outbreak in Brazil and spread to other countries in the Americas and elsewhere. In adults the infection is generally mild, although a link to Guillain-Barré syndrome has been established, but the virus can cross the placenta during pregnancy and cause microcephaly in the foetus. Human immunodeficiency virus (HIV) is the cause of acquired immune deficiency syndrome (AIDS). HIV is a retrovirus and infects CD4+ helper T lymphocytes. The destruction of these cells leads to immune deficiency and AIDS in which it is opportunistic infections, rather than HIV itself, that kills the patient. AIDS is a sexually transmitted disease for which there is no vaccine and no cure. Although many anti-HIV drugs have been developed these do not clear the virus from the body and if they are withdrawn the virus returns. Nonetheless, use of anti-HIV drugs is reducing HIV transmission and extending life expectancy of those infected.


19.       Preventing and treating virus infection:  Professor G L Smith

The lecture will describe how virus infections may be prevented by i) public health measures such as good hygiene, clean water, surveillance and quarantine, or ii) vaccination, and how virus infections may be treated with anti-viral drugs. Most of the lecture will be devoted to vaccination that remains the most effective means of preventing virus infections and this will be illustrated by the eradication of smallpox. The lessons learned from smallpox eradication and that are applicable to the control of other diseases will be discussed. The milestones in development of other virus vaccines used today and the properties of live, dead and passive vaccines will be described. Finally the strategies for development of new vaccines will be considered. 


20.  Characteristics of Fungi:  Dr A Carmichael

This lecture will describe the characteristics of fungi in general, including the structure of fungal cells, their reproduction and nutrition. Host defences against fungal infections will be reviewed, including conditions that impair anti-fungal defence. Methods of diagnosis of fungal infections and mechanisms of action of anti-fungal drugs will be reviewed, with discussion of the patterns of fungal infections, including commensals, superficial infections, subcutaneous infections and systemic (deep) infections. 

21. Systemic fungal infectionsDr A Carmichael
This lecture will describe the distinctions between systemic pathogens and systemic opportunists, with examples of the spectrum of serious fungal infections including environmental dimorphic fungi, Candida albicans, Pneumocytis, Cryptococcus and Aspergillus. 

Lent Term 2018

22.         Bacterial disease – Past, Present and Re-emerging:  Professor C Hughes

The spectrum and nature of bacterial infection and disease.  Bacterial transmission.  Sites of infection.

23.         Bacteria:  Prokaryotic Pathogens:  Professor C Hughes

Prokaryotic cell structure and function.  Growth and adaptability.  Genetics.

24.         Bacteria – Host Interaction:  Pathogenicity:  Professor C Hughes

Host defences against bacteria.  Bacterial mechanisms for colonisation, survival and transmission.  Pathogenicity is multifactorial and tightly regulated.

25.         Host Damage – Toxins, the Host Response:  Professor C Hughes

Protein Toxins.  Inflammation, immunopathology.

26.         Bacterial Pathogenicity in the Respiratory Tract:  Professor C Hughes

Examples of bacteria that colonise the respiratory tract.

27.         Bacterial Pathogenicity in the Gastrointestinal Tract:  Professor C Hughes

Examples of bacteria that colonise the gastro-intestinal tract.

28.         Combating Bacterial Disease:  Professor C Hughes

Public health, antibiotics, vaccines.  The nature and threat of drug resistance.

29.         Introduction to Parasitology, Helminths: Dr Jim Ajioka 

A short introduction to the range of protozoan and metazoan eukaryotic organisms that cause important human and veterinary infections, and then a focus on helminth diseases including schistosomiasis and their impact on global health. 

30.        Introduction to Parasitology, Protozoa: Dr Jim Ajioka 

The focus will be on two parasite groups, the Kinetoplasts and the Apicomplexa with specific examples of leishmainasis and toxoplasmosis.  The theme here will be how human activity and natural selection have changed the pattern of disease.

31.         Malaria: Dr Jim Ajioka 

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. Aspects of malaria morbidity and pathogenesis caused by P. falciparum will be discussed in the context of mechanisms of immunity, immune evasion and natural innate resistance to malaria in human populations living in disease endemic areas.

32.         Treatment and Control: Dr Jim Ajioka 

Chemotherapy has been a major part of treatment of parasitic diseases. Ivermectin and Artemisinin will be discussed as two contrasting examples of drug development and use in helminth diseases and malaria respectively.  Vector control plays a major role in vector borne diseases.  The massive distribution of Long Lasting Insecticide Nets and practice of Indoor Residual Spraying has made a big impact on malaria over the past 15 years.   

33.       Review: The Immune System against Pathogens: Dr A Kelly 

The immune response as an integrated system of defence against different pathogen groups.

34.       Vascular Reactions to Injury:  Professor N Coleman 

This lecture summarises the normal biology of haemostasis. It then describes the mechanisms by which haemostasis can be inappropriately activated leading to thrombosis and embolism. The roles that endothelial cells, platelets, altered blood flow and the coagulation cascade play in thrombosis will be examined. Finally, the clinical consequences of thrombosis and embolism will be introduced.

35.         Atherosclerosis:  Professor N Coleman

This lecture summarises the normal biology of arterial walls.  It then explores how normal artery walls are altered in atherosclerosis.  It will discuss the epidemiology and aetiology of atherosclerosis including positive and negative risk factors.  Then, the cellular and molecular pathology of atherosclerosis will be explored with emphasis on the roles played by lipoproteins, endothelial cells, smooth muscle cells, platelets and leucocytes.  Finally, the lecture will briefly introduce the clinical consequences of atherosclerosis.

36.         Ischaemia, infarction and their results:  Professor N Coleman

This lecture will firstly consider the various causes of inadequate blood supply to organs, followed by an exploration of the cellular consequences and the factors that influence outcome in affected tissues. Next, the lecture will consider the reversible and irreversible changes induced by ischaemia, including the stages of a developing infarct. The lecture will conclude with specific examples of infarction affecting key organs, such as the heart, brain and lungs.

37.         Amaemia:  Professor N Coleman
Anaemia is a clinical endpoint of multiple pathologies affecting red blood cells and/or their precursors. This lecture will consider some of the main causes of anaemia, including both genetic and environmental processes that reduce the production of red blood cells or increase their loss/destruction.

38.         The Nature of Cancer:  Dr P Edwards

Cancer as a disease. Brief introduction to cancer as failure of cell to participate in organisation of tissue as a result of altered genes. The distinction between benign and malignant tumours. Invasion and metastasis. The multistep nature of cancer development.  Colon and cervix cancer as examples. Tumour nomenclature. Incidence. How cancer causes disease and death. Presentation and screening.

39.         Cancer as an Evolutionary Process:  Dr P Edwards

Cancer develops by Darwinian evolution and clonal expansion. Oncogenes and tumour suppressors, using as example the Rb-1 pathway (controlling G1/S cell cycle checkpoint) and p53. Concept of genetic instability and its possible mechanisms: DNA repair defects, replication errors and mitotic errors. Hereditary predisposition to cancer including APC, mismatch repair deficiency, BRCA1 and BRCA2.

40.         Cancer Mechanisms:  Dr P Edwards 

The changes in cell behaviour in cancer, epitomised by the Hallmarks of Cancer concept (particularly the original 2000 version). Control of proliferation, including major signalling pathways; apoptosis; senescence and other stress responses, telomeres. Comparison with the Vogelstein model of colon cancer. Differentiation block, particularly in reference to leukaemias. Mechanism of metastasis (largely unknown and controversial).  

41.         The Cancer Genome: Dr P Edwards 

What sorts of gene get mutated and what sort of mutations they suffer, from chromosome translocations to point mutations, and how they alter the function of target proteins.  The complexity and variability of cancer genomes. Technology of genomics. Epigenetic ‘mutations’. Animal models to show effect of mutations in vivo.

42.         Causes of Cancer: Dr P Edwards 

Cancer seems mostly environmental, as it varies dramatically between different populations, and this is apparently due mainly to environment, rather than genetics.  Chemical carcinogens and their activation by metabolism; radiation and infectious agents. Attempts to identify carcinogens and quantitate their potency. Brief coverage of human cancer-associated viruses.

43.         Cancer Therapy: Dr P Edwards

A forward-looking survey of the prospects for cancer therapy.  Classic cytotoxic therapies and how they might work. Targeted therapies, including anti-tyrosine kinases and anti-genetic instability approaches exemplified by PARP inhibitors. Resistance. Engineering viruses to kill cancer cells. Exploiting immune system via attempts to block tolerance.