Pathology in rhythm and rhyme

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  • Transplant turmoil

    Breaking barriers-Suppressing revolt

    While immunity is intrinsically designed to protect the self against foreign antigens, in the era of transplantation – allograft or xenograft, whole organ or stem cells – a deliberate attempt is made to suppress immune pathways that would reject the transplant. The barrier to tolerating the graft is broken by suppressing the expected revolt by cellular and humoral immunity, enabling successful survival and functional engraftment. The rare possibility of the donor being a twin of course obviates the possibility of rejection. To begin with blood group and HLA cross-matching reduce the possibility of graft survival by minimizing key donor antigens that the donor or recipient APCs will present to the T-cells to. In contemporary practice, renal transplantation is most frequent and well established, followed by liver, heart, pancreas and others. Iatrogenic immunosuppression with a host of drugs targeting immune pathways, has a cost: a lifelong follow-up to monitor rejection- hyperacute, acute and chronic; usual and unusual opportunistic infections with morbid and mortal outcomes and, appearance of neoplasia of certain types unique to the transplantation setting, often triggered by activation of oncogenic viruses. A full account of these can be found in standard textbooks and review articles: some suggestions are placed at the end of this post.

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  • Immunity Implosion

    When self-defense becomes self-harm

    The Immune system, protects the human body from a range of adverse agents – infectious or non-infectious but is also equipped with a sophisticated range of options to prevent or obstruct injury to its own tissues by recognizing self as opposed to non-self. The failure of one or more mechanisms of self-tolerance results in autoimmunity (AI): a relentless targeting of tissues of single or multiple organ systems, with a higher risk in females, summarized in the poem below. Enablers of autoimmunity are genetic predisposition, complemented by environmental triggers. T-cell or B-cell dominant pathways (or both), execute the damage. A spectrum of clinical entities result: one of the best examples, suspected clinically and confirmed by laboratory tests, is Systemic lupus erythematosus (SLE), the prototype of a multi-system connective tissue disorder or collagen vascular disorder as this group of diseases are often referred to. Despite advances in understanding the cellular and signaling mechanisms, treatment options are at best disease-modifying and cures are not yet visible on the therapeutic horizon, attesting to the complexity of disease pathways. On the other hand, useful applications exist in the realm of oncologic practice where interrupting self-tolerance has been used as a precision medicine tool to treat tumors as a form of targeted immunotherapy.

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  • Safeguarding Survival – readymade or bespoke

    Immunity to usual and unusual offenders

    The Immune system’s structure and function unlike most organ systems in the body, is distributed (for surveillance) yet united in cross-talk within its components and receptivity to adverse stimuli. With a phenomenal capacity for explosive growth and diverse antigen recognition (commensurate with the severity of provocation) it closely resembles the haemopoietic system, with which it shares a dynamic co-location and co-performance. Whether innate or acquired, in latency, controlled response or in excess, Immunity’s cellular and extracellular mediator components are stimulated in response to infections or anything identified as the other as opposed to the self. This controlling and eliminating function is supported by a memory function for sustained resistance to repeat encounters. In pathological terms, the inappropriate or excessive overdrive of precisely the same mechanisms, unchecked if regulatory controls fail, allow diseases with an immune basis to emerge. In this post, Hypersensitivity, is in focus. The original Gell and Coombs classification system of 1963 (with modifications) groups these aberrant hyper-immune reactions based on the predominant immune mechanism into 4 classes. The result is a transformation of physiological protection to pathological tissue destruction – local/systemic, single/multiorgan, acute/chronic – with potential for relapse and recurrence.

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  • Humans decoded

    What our genes foretell

    From Mendel’s 19th century research into inheritance in pea plants to groundbreaking discoveries supported by technology resulting in the Human Genome Project in the 21st century, within the last century-and-a-half, we have achieved a refined understanding of the impact of Genetics on human disease, inherited or acquired. As the anatomy of chromosomes, DNA and RNA, unraveled, the genetic basis of multi-organ syndromes and single organ diseases has been established. Some are defined by a clinically recognizable phenotype (Down and Marfan syndrome); others due to single gene defects encoding for critical proteins like enzymes, require neonatal testing or may take months or years to be diagnosed. Evolution of cancer research benefited from the parallel discoveries of DNA, RNA and cell signaling, which revolutionized the understanding of cancer biology. Clinically significant genetic diseases and genetic changes in cancer cells, whether hereditary or acquired, are diagnosed with ease today. Research, aided by Big Data and sophisticated technology, has enabled gene manipulation and targeted therapy in the era of Personalized Medicine.

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  • Cell death: a harbinger of irreversible injury

    The final bow: many ways to die

    Cell or tissue death follows irreversible injury due to a variety of etiologies. Apoptosis, morphologically a ‘falling out’ of a single cell from its surrounding tissues, is programmed and tightly regulated. In both physiological and pathological situations, its significance lies in leaving surrounding tissues undisturbed with absence of an inflammatory response: scavengers (macrophages) quietly removing the cell debris. Necrosis, however, entails significant loss of tissue volume, evokes an inflammatory response, manifests with local and/or systemic clinical symptoms and signs and, eventually, affects tissue structure (clinically and on imaging) and function (altered hematologic, biochemical and immunologic parameters). Macroscopic appearances range from the black discoloration of gangrene – dry/wet/gas; the fluctuating consistency of an abscess accompanied by the classical signs of inflammation; cheesy transformation of caseous necrosis etc. Microscopic examination of affected tissues may show single cell drop out or cell fragments (apoptosis) versus the ghost outlines of coagulative necrosis, collections of neutrophils with no intact cells in liquefactive necrosis or the caseating centers of necrosis in granulomas due to mycobacterial and some fungal infections.

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  • Hemodynamic disturbances: infarction

    Interruptio fluxus sanguinis: a weapon of mass tissue destruction

    The abrupt obstruction of arterial blood supply to target organs leads to coagulative tissue necrosis – infarction. Venous obstruction or compression can have similar consequences. Either event constitutes an emergency, especially in tissues which depend for vitality on oxygenation like the brain, heart and kidneys. The time from onset of symptoms to relief of obstruction, is critical to minimize tissue death, morbidity and mortality. Within the window period of tissue viability, which varies with different organs, a host of medical, surgical and interventional options exist.

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  • Haemodynamic disturbances: thromboembolism throws a spanner in the wheels

    Extravascular Blood loss or block of Intravascular blood flow

    Vessel wall damage due to injury or disease causes haemorrhage, the breach is easily sealed with a localized primary hemostatic plug of platelets reinforced by a sturdier secondary plug with fibrin derived from the activated coagulation cascade. In larger structural damage, with significant volume loss, emergency treatment is required to prevent shock, with a potentially fatal outcome. Inside intact vasculature, blood flow is smooth and steady ensuring delivery of nutrition, oxygen, immune-mediating cells and soluble factors, and fluid to tissues. Activation of the coagulation cascade generates solid masses, thrombi, localized or generalized, static or dislodged as emboli with devastating consequences in distant organs. The Virchow’s triad of blood stasis or turbulence; endothelial disruption, hypercoagulability, whichdefines the classical pathophysiologic mechanisms that mediate the formation of thrombi due to a variety of triggers, has stood the test of time. The list of etiologies, that stimulate one or more of the three mechanistic pathways, is long – many find mention in the poetic summary below. Acute or chronic, management of bleeding, thrombosis and embolism is critical and challenging.

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  • Fluid derangements – excess is egregious

    Too much of a good thing: intracellular, extracellular, extravascular fluid excess

    Water is one of the key components of the milieu interior: when disbalanced in quantity and location, a diseased state is inevitable. Naturally confined in optimum quantities inside body cells and key to maintaining flow inside the vascular network, increased hydrostatic pressure (cardiac failure, inflammation, vascular compression or obstruction), reduced colloid oncotic pressure (hypoproteinemia: nutritional, decreased synthesis or excessive loss) or poor lymphatic drainage (block or interruption by surgery) are the salient etiologies for fluids to leave vessels. The clinical sign of edema – pitting – elicited most often in dependent parts of the body is ominous. This external sign when slow to manifest still conceals serious organ disease and morbidity due to functional compromise of internal organs. In rapid accumulations, it can be life threatening!

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  • Chronic Inflammation challenges time and outcomes

    When the initiating injury is slow, immunity is slow to awaken

    A host of etiologies evoke chronic, not acute inflammation. Some infections, metabolic products, autoimmune reactions etc. are slow to be recognized by the immune system. Instead of the classical neutrophil response in acute inflammation, in chronic inflammation it is mononuclear and takes time. The net result – a long latent period passes as this slow response gathers momentum to liberate cytokines and damage tissues significantly to produce localizing symptoms and signs or systemic reactions like fever, malaise and weight loss. The slower the evolution, more protracted the course, more extensive the damage, longer the requirement for therapy and, not least, more morbid the outcome with long lasting damage to structure and function.

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  • Inflammation needs mediation

    Chemical mediators: bane or boon?

    Accompanying the early vascular and cellular responses to inflammation, several pre-formed and newly synthesized chemical mediators flood the site of tissue injury. They originate from endothelial cells, immune cells and native stromal cells. At first, they amplify the inflammatory response to overcome the etiology and its tissue damage. Later, they enable removal of dead material, and promote tissue regeneration and repair.

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