IMMUNOPATHOLOGY Immunopathology is one's immune system reaction.

Symptoms of immunopathology are unique to a patient and can include: fatigue, muscle weakness, rash, headache, photosensitivity, pain anywhere, numbness, nausea, diarrhea, constipation, ringing in the ears, toothache, sinus congestion, nasal stuffiness, fever/chills, flu-like bodyache, cough, irritability, depression, sleep disturbances and brain fog. Any symptom, including abnormal lab results, that correlates with MP therapy is most likely due to immunopathology. Patients who are less sick will have comparatively less strong immunopathology. The increase in symptoms due to immunopathology typically begins 1-24 hours after the minocycline dose and usually dissipates 12-24 hours before the next antibiotic dose. Many patients find that the reaction is strongest on the second day. As opposed to the disease itself, which progresses over the course of decades, immunopathology symptoms usually flare quickly. However, dramatic waxing and waning of immunopathology does not always happen. An increase in symptoms may be constant. Immunopathology is sometimes mistaken for an allergy to a MP antibiotic. A number of strategies are available for managing immunopathology. Expected symptoms of immunopathology When bacteria are killed, endotoxins and cytokines are released at the site of the infection. This contributes to a sense that one's original disease is getting worse. In fact, the increase in symptoms is only temporary. Although these symptoms may be similar to one's disease, unlike disease symptoms, they are a sign that something is being accomplished: the Th1 pathogens are being killed. The immunopathological reaction is caused by release of toxins and the apoptosis (die off) of infected cells. People with effective detoxification and elimination systems may not experience significant aggravation of symptoms. Some of my patients just experience gradual improvement in health. Others experience mild loss of stamina, periodic night sweats or emotional swings. I firmly believe that Th1 patients no matter what their diagnosis react similarly. I would suggest evaluating present condition with that which was present prior to starting the MP. Most patients with a diagnosis of borrelia have significant physical or cognitive loss and have received other therapies prior to them starting the MP. Some of these therapies can result in delayed or reduced immunopathological reactions. Greg Blaney, MD As evidenced by high rates of depression and anxiety in the population at large, the brain itself is a frequent site of chronic bacterial infection. One of the challenges of having neurological

immunopathology is a lack of awareness about the role infection and immunopathology play in one's mood, cognitive abilities, and ability to think clearly. It is very common for patients with neurological immunopathology not to recognize that their recovery will involve the temporary exacerbation of these types of symptoms. One's life events play a role in, say, depression, but often enough they are not the driving force behind it. Along with neurological immunopathology, cardiac immunopathology and respiratory immunopathology are potentially life-threatening. Patients who have, or worry that they may have, these symptoms should work particularly closely with their physician and proceed on the MP cautiously. Unexpected symptoms of immunopathology The MP can't create new inflammation because it can't make bacteria appear where there weren't any before. The presence of new symptoms is a clear indication that bacteria are being targeted in areas of the body not known to be infected. In the absence of undergoing some kind of curative therapy like the MP, it seems probable that these sites of sub-clinical infection would in time be part of the disease process. If extra Benicar reduces a symptom, one can be sure it is due to immunopathology. But, lack of response to Benicar does not rule out immunopathology. Palliative medication may reduce symptoms of immunopathology also. Necessity of immunopathology Immunopathology is not a side effect of the MP not in the traditional sense anyway. Also, the MP does not cause an exacerbation of disease symptoms. Patients are hardwired to equate symptoms with disease, but what many do not realize is that all disease symptoms are the result of an immune system response. A rise in intensity of symptoms is not a sign that the disease process is advancing, but an indication that the immune system is active and killing bacteria. If a person gets infected with a virus, the rise in symptoms he or she displays is not caused by the virus, but the response of the immune system to the virus. The symptoms of food poisoning including diarrhea and vomiting are very unpleasant, but are extremely effective in rapidly eliminating toxins. The Jarisch-Herxheimer response, a term which is sometimes used interchangeably with immunopathology, has been documented as necessary to recovery in over 10 diseases, to say nothing of evidence supporting the MP's effectiveness. Based on everything we know about the way the bacteria have parasitized the immune system, and the way they affect the body's molecular chemistry, I am sad to say that it seems 'no pain, no gain.' I suspect we will find some palliative techniques as time goes by, especially for pain, but the starting point is relatively unpalatable, I am afraid. This is, of course, one of the reasons why nobody has been able to develop a therapy until now. Until you understand the pathogenesis, there is no way that 'no

pain, no gain' makes any sense. But when you understand how the bugs are wreaking their havoc - it all becomes crystal clear. Trevor Marshall, PhD A potent anti-inflammatory, Benicar should palliate negative symptoms and minimize any tissue damage caused by the disease process. Assessing immunopathology Immunopathology is necessary for making progress on the MP. Throughout the course of one's treatment, the goal is to generate a tolerable level of immunopathology. But how does one determine if immunopathology is tolerable or intolerable?

ACE (Angiotensin Converting Enzyme) is a marker, which reflects the severity of inflammatory diseases such as sarcoidosis. In this graphic, taken from a patient interview on Bacteriality, it's possible to see how one patient's ACE, waxed and waned over the course of the MP. Note that the ACE continued to fall. Using lab tests to track immunopathology With chronically ill patients, it is common to disassociate from one's feelings and therefore it can be difficult to determine the sometimes subtle shifts associated with Herx reactions. My use of lab tests is to help determine pace of therapy especially if degree of Herx reaction is difficult for patient to interpret. Greg Blaney, MD

Abnormal lab work or ECG tracing may reveal unacceptable silent immunopathology. In that case, monitor these signs regularly and use them as a guide to gauge pace of therapy. Other ways to assess immunopathology Even for diseases that have ideal measures for tracking immunopathology, it is sometimes possible to have a flare in symptoms and not know why. This is particularly true for patients whose diseases have a strong mental component and have trouble thinking critically about their illness. Sometimes the onset of uncomfortable symptoms simply cannot be explained, only managed. Other times though, it is a factor within a patient's control. These questions might help patients gain insight into why they feel worse.

PATHOGENESIS OF GLOMERULAR DISEASES

At the end of these two lectures (Pathogenesis of the glomerular diseases and Pathology of specific glomerular diseases) students should have understanding of: (1) (2) (3) (4) (5) (6) Ultrastructure and functions of glomerular capillary wall Pathogenetic mechanisms of glomerular damage Classification of the glomerular diseases Clinical expressions of the glomerular diseases Pathological nomenclature of the glomerular diseases Some of the common specific glomerular diseases and their outcome

Glomerular disease encompasses a spectrum of morphological changes resulting from a wide variety of etiological factors. Majority of the glomerular diseases are immune-mediated.

PATHOGENESIS OF GLOMERULAR DISEASE

10 Immunopathogenetic mechanism: - Initiator of the disease process by deposition/formation of immune complexes (1) Antibody mediated (2) T-cell-mediated 20 immunopathogenetic mechanism: - Actual mediation of the disease (1) Role of complement (2) Role of neutrophils (3) Role of monocytes/macrophages (4) Role of coagulation systems

10 Immunopathogenetic mechanisms:

Antibody mediated: o Circulating immune complex deposition (granular immunofluorescent pattern) o In-situ immune complex formation (I) Intrinsic fixed glomerular antigen (1) Normal component of glomerular basement membrane, linier immunofluorescent pattern: Anti-glomerular basement membrane-antibody disease (2) Podocyte antigen, granular immunofluorescent pattern Immune complex glomerulonephritis (II) Intrinsic and/or extrinsic non-glomerular; non-fixed antigen - Planted antigen, granular immunoflorescent pattern Intrinsic i.e. endogenous proteins Extrinsic i.e. products of bacteria, viruses, parasites, foreign proteins etc. Immune complex glomerulonephritis T-cell-mediated: T-lymphocytes are essential for cell-mediated and antibody-mediated immune response. Thus it is responsible for both induction and mediation of renal disease that are caused by immune responses. This may occur through regulation of B-cell differentiation and antibody production or by local cell-mediated immunity i.e. delayedtype hypersensitivity reaction. The later is initiated by CD4+ cells by activating monocytes/macrophages which produces cytokines: IL12, IL2, INF- and TNF- which are powerful inflammatory mediators causing injury. CD8+ cells acts by their cytotoxic ability.

20 Immunopathogenetic mechanisms:
(1) Role of complement: Complement is activated by immune complexes (classic pathway) or by complex polysaccharides (alternate pathway). C3 & C5 are chemoattractant for leukocytes, neutrophils in particular which causes damage by releasing proteolytic enzymes and by generating reactive oxygen metabolites. Terminal complement components C5b-9, membrane attack complex (MAC) causes injury by basement membrane lysis. (2) Role of neutrophil: Neutrophils can cause damage to the membrane and cause proteinuria by generating reactive oxygen metabolites and by releasing of proteolytic enzymes. They can also mediate acute changes in glomerular hemodynamics i.e. alter glomerular filtration by mechanical obstruction of capillary lumens, attaching themselves to the endothelium and in tern stripping the same from the underlying basement membrane reducing the available surface areas for filtration.

(3) Role of monocyte/macrophage: These groups of cells play major part in acute as well as chronic inflammatory process by producing various cytokines, reactive oxygen metabolites, plasminogen activator etc. The resident macrophages may participate in the local presentation of antigen in delayed-type hypersensitivity reaction. They are also responsible for hypercellularity of the glomerular tuft particularly in diffuse proliferative glomerulonephritis, crescentic glomerulonephritis etc.

(4) Role of coagulation system: Glomerular deposition of fibrin is important factor in causing proliferation of parietal epithelial cells forming crescent. Intra-glomerular fibrin deposition may lead to glomerulosclerosis.

COMMONEST IMMUNE-MEDIATED GLOMERULAR DISEASE IS IMMUNECOMPLEX GLOMERUONEPHRITIS

Clinical expressions of the glomerular diseases:

Patients can present with any one of the following or combination of more than one:(1) (2) (3) (4) (5) (6) Asymptomatic proteinuria Microscopic hematuria Acute renal failure Chronic renal failure Acute nephritic syndrome Nephrotic syndrome

Acute nephritic Syndrome comprises of:Hematuria Azotemia Proteinuria Edema Hypertension

The Nephrotic Syndrome is characterized by:Proteinuria > 3.5 gms/24 hrs Hypoalbuminemia < 25 g/l Edema Hyperlipidemia Lipiduria

Some of the common causes of nephrotic syndromes are:Minimal change disease (common in children) Membranous glomerulonephropathy (common in adults) Mesangiocapillary (membranoproliferative) GN Focal & Segmental glomerulosclerosis Systematic diseases including: Diabetes mellitus Systematic lupus erythematosus (lupus nephritis) Amyloidosis etc.

Terminology used in glomerular diseases DiffuseFocal Segmental A lesion involving all or nearly all glomeruli (> 80%) A lesion involving some but not all glomeruli (< 50%) A lesion involving portion of glomerulus (i.e. some capillary loops remain uninvolved) Sclerosis A lesion of the glomerulus where there is increase in fibrillary material laid within mesangial areas with collapse of capillary loops and condensation of basement membrane. Crescent:Cellular A lesion consisting of cellular proliferation of parietal epithelial cells filling part of Bowmans space. Fibro-cellular A lesion which is similar to cellular crescent but with variable amount of fibrillar material. Fibrous A lesion within Bowmans space which is predominantly composed of fibrous tissue i.e. scarred cellular/ fibrocellular crescent. Classification of Glomerular Disease Clinical Morphological Etiological Immunopathological

Basis of Classification Immune complex glomerulonephritis Anti-GBM-antibody diseases

Immune complex glomerulonephritis Associated with infection Post-streptococcal GN Post-infections GN

Associated with systemic diseases Systemic lupus erythematosus i.e. lupus nephritis Primary Glomerular diseases Idiopathic membranous GN Mesangiocapillary (membranoproliferative) GN

Anti-GBM-antibody disease Goodpasture syndrome Disease with immune mechanisms without IC formation or anti-GBM-antibody development Minimal change disease Focal & segmental glomerulosclerosis.

PATHOLOGY OF SPECIFIC GLOMERULAR DISEASES

Acute (diffuse proliferative) glomerulonephritis
It is also described as post-streptococcal / post-infectious glomerulonephritis. It is a form of immune-complex glomerulonephritis and is characterized histologically by diffuse proliferation of glomerular cells with or without influx of polymorphs. The disease is more common in children & young adults and usually presents as acute nephritic syndrome. One can elicit h/o preceding infection i.e. sore throat or skin sepsis. The most common organism responsible is group A -hemolytic streptococci but other organisms have been identified. Serological investigation shows rising titers of ASO and low levels of C3. Electron microscopic examination of the glomeruli will show electron dense subepithelial immune complex deposit classically known as subepithelial hump. This disease is usually self limiting and only less then 5% of the patients may either progress to rapidly progressive glomerular disease (crescentic glomerulonephritis) or to chronic renal disease.

Lupus nephritis
As much as 70% of the patient suffering from Systemic Lupus Erythematosus (SLE) will show renal involvement. This is an autoimmune disease, also an example of immune-complex glomerulonephritis where the antigen is an endogenous protein. The presence of antibodies to nuclear protein i.e. anti-nuclear-antibody (ANA) to double stranded DNA is a hallmark of the disease. The hallmark of the disease in tissue is hematoxylin bodies.

The disease is more common in women, particularly of African descent, in child bearing age group with F:M ratio being 9-10:1.The patients can present as significant proteinuria ( 200mg/24 hr.); nephrotic syndrome; acute nephritic syndrome etc. The renal prognosis will depend on histological features i.e. diffuse proliferative type of histology will carry much worse prognosis then diffuse mesangial proliferative type of histology.

Idiopathic membranous glomerulonephritis

Most common cause of nephrotic syndrome in adults and is characterized by diffuse thickening of the capillary walls due to extensive subepithelial immune-complex deposition which can be identified on light, electron and immunofluorescence microscopic examinations. The disease is insidious in onset and shows slow progression to reach to chronic state eventually. The management of this disease remains controversial. When the disease is associated with other systemic diseases, it is no longer idiopathic but will be known as secondary type of membranous glomerulonephritis. This occurs commonly in following conditions: - Drug therapy, after prolonged gold therapy, penicillamine or NSAIDs etc. - Systemic Lupus Erythematosus i.e. lupus nephritis - Infections: Hepatitis-B, or C etc - Secondary to malignant tumors, especially epithelial tumors

Mesangiocapillary (Membranoproliferative) glomerulonephritis

This disease is also known as hypocomplementemic glomerulonephritis as there is low levels of C3 in almost all the patients. This is a disease of children in general but can occur at any age. The classical presentation of this disease is nephrotic syndrome but can also presents as acute nephritic syndrome and is characterized by enlarged, hypercellular glomeruli with accentuation of the lobules, with marked thickening of the capillary wall which shows double contour or tram-track appearance. There are subendothelial electron-dense deposits seen on electron microscopy. The course of this disease is one of slow progression and is generally not responding to corticosteroid or immunosuppressive therapy and eventually ends in chronic renal failure.

Minimal change disease

Is a commonest cause of nephrotic syndrome in children in whom this disease occur frequently. Despite massive proteinuria, the renal function remains normal. Over 90% of patients are corticosteroid sensitive while small numbers of patients are corticosteroid dependent or resistant. The later can be treated by immunosuppressive agents. The disease is characterized by normal appearing glomeruli on light and immunofluorescence microscopy and the only

abnormality detected is effacement of epithelial cell foot processes which is identified on electron microscopy only. No immune-complexes are identified and so the disease is not an immune complex in origin but several associated features suggests immune mediation. The current hypothesis is that the cell-mediated immunity seems to play an important role where Tlymphocytes are said to produce vascular permeability factor which is responsible for massive proteinuria.

Chronic glomerulonephritis
It is an end stage disease in which there is wide spread (>90%) glomerulosclerosis associated with extensive tubular atrophy, interstitial fibrosis, mononuclear cell infiltration and vascular changes of benign hypertension. The pelvis will remain unaffected (unlike chronic pyelonephritis). This results in marked reduction in glomerular function leading to chronic renal failure. At this stage no underlying glomerular pathology can be determined.