First Pass Miss Exam 2 Flashcards
What cells in the tissue release inflammatory cytokines initiating the innate immune response?
Mast cells and dendritic cells (note that DCs make IL-1 / TNF)
What cytokines does the Th17 subset of CD4+ T helper cells secrete and what does this do? What causes formation of this subset?
Secretes IL-17 -> recruits inflammatory response via neutrophils and monocytes
Induced by TGF-beta in combination with IL-6
What are the two types of Treg cells and what cytokines do they release?
All secrete IL-10 / TGF-beta, which suppress the immune response
Natural T-regs = CD4+,CD25+, FoxP3+ T cells which were developed in thymus, suppress autoreactive T cells
Adaptive regulatory T cells = Originally CD4+ cells which are induced to express CD25 marker in the periphery, typically involved in mucosal immunity (i.e. MALT)
What cytokines does the Th1 subset of CD4+ Tcells secrete and what does this do? What causes formation of this subset?
Secretes IFN-y -> activates macrophages, induces class switching to IgG, suppresses Th2 response
Induced by macrophages secreting IL-12, IFN-y
Where are follicular dendritic cells present and what is their function?
Exist in germinal centers of lymphoid follicles, function to hold onto antigens for long periods of time and present these to B lymphocytes, promoting their activation. They sit there and accept antigens from them and hold onto them while they mutate and adapt.
-> let the B cells undergo somatic hypermutation and affinity maturation
What cells have MHC Class 2 and what can increase their expression?
Located on B cells, dendritic cells, and macrophages, but only constitutively expressed in dendritic cells. Upregulated via IFN-y.
How do NK cells activate antibody-dependent cell-mediated cytotoxicity?
Their Fc receptors bind an immunoglobulin which has bound a cell (part of adaptive immune response), and they release perforin / granzymes into the target cell. Can also use FasL death receptor.
What is Type 1 Hypersensitivity and what antigen-presenting cells are involved in the sensitization phase? How does this occur?
Immediate Hypersensitivity Reaction
2 APCs involved
- Dendritic cells - present allergen via MHC Class II, while secreting IL-4 -> turn naive T-cells into allergen-specific Th2 cells, with clonal expansion
- B cells - bind allergen via their BCR’s, internalize, and present via MHC Class II. This further activates Th2 cells
it’s all about making sensitized Th2 cells which induce IgE via IL-4
What two processes mediate the late phase reaction of Type 1 hypersensitivity?
- Activation of phospholipase A2.
From arachidonic acid: make leukotrienes B4,C4, and D4 and PGD2 from cell membrane
From phospholipids: makes platelet-activating factor. - Secretion of cytokines/chemokines: i.e. IL-4, IL-5, TNF, and IL-1 -> proinflammatory and pro-TH2.
What are the clinical features that can result from increased vasodilation, increased edema, bronchoconstriction, and increased glandular / mucinous secretions? (Type 1 hypersensitivity)
Vasodilation -> localized erythema which may cause shock
Edema -> hives on skin, or nasal / laryngeal edema
Bronchoconstriction -> wheezing / airway constriction following bronchospasm
Glandular / mucinous secretions (from mucinous metaplasia of PSCC) -> rhinorrhea and even mucous plugs
What is the main difference between Type II and Type III hypersensitivity?
Type III hypersensitivity is forming immune complexes to a SOLUBLE antigen, which may be circulating or planted
Type 3: Complement will ALWAYS be involved in tissue damage.
Type 2: Can involve antibody-only processes (cellular dysfunction i.e. Graves disease or myasthenia gravis, or ADCC like killing tumor cells)
What causes secondary damage following complement in Type III hypersensitivity?
Degranulation and ROS via PMNs and macrophages, with resultant endothelial damage and activation of primary / secondary hemostasis and coagulation cascade.
(All primary damage is complement-mediated)
What are the two types of Type IV hypersensitivity? Give two examples of each.
- Delayed-type hypersensitivity
- > contact dermatitis due to poison ivy (atopic dermatitis is Type 1)
- > tuberculosis skin testing
- due to proliferation of CD4+ Th1 type cells - Cytotoxic T-cell mediated hypersensitivity.
- > Graft-versus-host disease
- > Hashimoto’s thyroiditis
- due to proliferation of CD8+ Tcells
How does the sensitization phase of (delayed-type) Type IV hypersensitivity differ from Type I hypersensitivity?
Type I hypersensitivity - IL-4 stimulates CD4 differentiation into Th2 cells, which facilitate B cells to make IgE
Type IV hypersensitivity - IL-12 stimulates CD4 differentiation into Th1 cells, which facilitate secretion of IFN-y
What occurs in the effector phase of delayed-type Type IV hypersensitivity?
- Activation and proliferation memory Th1 cells
- > secrete IFN-y, IL-2, TNF, and chemokines to recruit monocytes - Monocytes are activated to M1 macrophages via IFN-y, and stimulate further Th1 proliferation via their IL-12. More TNF, IL-1, and chemokines are made.
What are the initial and late histopathological findings of Type 4 hypersensitivity effector phase?
- Initial -> diffuse infiltrate of Th1 cells
- Later -> collections of activated macrophages, surrounded by Th1 lymphocytes. This is the granulomatous inflammation we know and love.
What is the direct pathway of graft recognition?
Usage of donor’s APCs to stimulate host CD4 or CD8 T cells via the proper MHCs to result in activation
- CD8 cells are activated by cytoplasmic peptides of the graft APCs being presented on MHC Class I, which are recognized as foreign by the receipient’s T cells.
- CD4 T cells are activated by APCs presenting any extracellular peptides on MHC Class II, thus allowing recognition of donor MHC.
What is the effect of the direct pathway in terms of graft rejection?
Results in acute rejection (cell-mediated)
CD8 T cells directly kill graft cells
CD4 T cells activate macrophages via IL-2 and IFN-y and amplify the inflammatory response, leading to graft damage
What is the indirect pathway of graft recognition important for, and which type of T cell participates? Why?
Important for development of chronic rejection
CD4+ T cell participates, but not CD8 T cell since the indirect pathway relies on host APCs presenting to T cells. Host APCs will not be able to present graft material as intracellular / cytoplasmic foreign material, only extracellular (CD4 pathway only).
What type of hypersensitivity is hyperacute graft rejection, and what does it look like?
It is a type 2 hypersensitivity (tissue antigen, insoluble), looks like type 3 because of high levels of complement deposition in tissues, but it’s the donor’s tissues.
- > edema
- > acute inflammatory infiltrate
- > endothelial cell damage, fibrinoid necrosis, hemorrhage, and thrombosis
- > tissue infarct
What are the two primary mechanisms of acute rejection, and which is more easily treatable?
- Cell-mediated - due to T-cell overactivity (from direct pathway)
- > easily treated by increasing immunosuppression (most immunosuppressives effective against T-cell proliferation) - Humoral - due to antibodies formed after transplantation. More difficult to treat.
How does acute, cell-mediated rejection (Type 4) appear histologically?
Interstitial inflammatory infiltrate with T cells and macrophages, injuring tubules (tubulitis) and vascular endothelium (endothelitis and edema)
How does acute, humoral rejection appear histologically? There are really two presentations here, and one is more common.
Since it is due to antibodies, it usually appears exactly like hyperacute rejection (just later).
- Most common - A type 2 hypersensitivity which looks like type 3 w/ associated vasculitis and fibrinoid necrosis.
- Alternatively, can present with vascular intimal thickening via foamy macrophages which are recruited by antibodies which cannot fix complement (low avidity). Fibroblasts and SMCs will proliferate due to cytokine production and lead to tissue atrophy. Not associated with vasculitis, more vessel stenosis by thick intima.
What immunologic mechanism is behind chronic rejection?
Indirect pathway of CD4+ T cell activation
-> activated macrophages and APCs present alloantigens from broken down graft / areas of ischemia, which leads to further T cell activation and subsequent inflammation & breakdown of graft for more antigen presentation.
Other than ABO compatibility, what three things are done to prevent solid organ transplant rejection?
- HLA matching (especially in renal transplants)
- Immunosuppressant therapy
- Induction of immune tolerance by using agents which selectively block co-stimulatory molecules, inducing anergy
Give two reasons why a little bit of graft versus host disease (GVHD) might be good? (Allogeneic stem cell transplant)
- Reduces chances of graft rejection -> remaining recipient T cells which were not ablated will be killed by the donor’s immune system
- Donor cells are often given in malignancy conditions, and if the graft immune system can recognize the host tumors, it can serve better anti-tumor properties
What are the common manifestations of GVHD in terms of which tissues are affected?
- Skin -> often maculopapular rash acutely, with dermal fibrosis chronically
- Liver - often jaundice due to injured bile ducts
- Mucosal surfaces like GI tract, eyes, and mouth can be damaged leading to N/V, eye dryness
- Lymphoid organs -> destruction of thymus and LN
What are some non-immunologic mechanisms of graft rejection?
- Insufficient nephron mass (small kidney in bring person leading to glomerular hyperfiltration)
- Reperfusion injury at engraftment
- Infections due to immunosuppressive therapy
- Immunosuppressive drug toxicity
- Increasing age of recipient with atherosclerosis / hypertension
How does peripheral anergy of B cells occur?
Usually due to lack of self-reactive helper T cells.
How does activation-induced cell death of T-cells occur?
Initially, T-cells are resistant to Fas-mediated apoptosis. However, as they become overactive, they will T cells will overexpress Fas / FasL, allowing for paracrine / autocrine deletion via apoptosis.
How can autoimmune conditions become progressively worse after initiation?
Via the process of epitope spreading -> antigens not normally seen without tissue damage will become expressed, further continuing lymphocyte activation vs self-antigens
What two auto-antibodies are very specific but not sensitive for SLE?
- Anti-dsDNA
2. Anti-Smith antigen
What are the clinical manifestations of these three antibody types? What type of hypersensitivity are these, when relevant?
- Anti-nuclear antibodies (ANAs) - immune complex formation in small blood vessels (i.e. glomeruli) - Type III hypersensitivity
- Antibodies vs formed blood elements (RBCs, platelets, WBCs) - anemia, thrombocytopenia, or leukopenia (Type II hypersensitivity)
- Antiphospholipid antibodies
- > delayed coagulation in vitro -> lupus anticoagulant antibodies
- > hypercoagulability in vivo -> antiphospholipid antibody syndrome
What kidney condition does SLE cause and why? What are “wire loops” of SLE?
Diffuse proliferative glomerulonephritis, due to Type 3 hypersensitivity from antinuclear-Ab complexes, and resultant fibrinoid necrosis, acute inflammation, and thrombosis
Wire loops: Very thick glomerular capillaries seen in SLE due to extensive immune complex deposition
Other than skin, kidneys, and arteries, give a few other places where immune complexes are known to cause problems in lupus?
- Joints -> ultrafiltrate of plasma, type 3 hypersensitivity
- Serosal surfaces -> fibrinous inflammation of peritoneum and especially pericardium
- Heart -> especially valves (vegetations) and pericardium (pericarditis)
What does the homogenous vs speckled indirect immunofluorescence pattern mean
Homogenous - antibodies to diverse nuclear constituents, including DNA and non-DNA elements
Speckled - also nonspecific, antibodies to non-DNA nuclear components
What does a nucleolar pattern mean via the ANA indirect immunofluorescence test? rim? Centromere?
Nucleolar - nucleolar RNA antibodies -> seen with systemic sclerosis
Rim - dsDNA -> specific for SLE
Centromere - CREST = limited systemic sclerosis
What is the highly local lupus variant, and what are its clinical manifestations? How do lesions appear grossly and microscopically?
Chronic discoid lupus erythematosus -> a scarring dermatosis
Involvement of sun-exposed skin on face and scalp, with no antibodies in non-lesional skin
Lesions will appear as scaly skin plaques with red border, and will form scars.
Microscopically, there will be epidermal atrophy, and chronic inflammation around the DE junction (involves basal cells)
How does subacute cutaneous lupus erythematosus differ from chronic discoid lupus erythematosus?
Different ANA antibodies cause it, and it results in a mild, non-scarring rash.
Importantly, it will also have some systemic manifestations (not totally local)
What antibodies are associated with each of the following disorders: CREST subtype of systemic sclerosis Drug-induced Lupus Sjogren's syndrome Mixed Connective Tissue Disease
CREST - Anti- Centromere
Drug-induced lupus - antihistone antibody
Sjogren’s = Ribonucleoproteins SS-A / SS-B (anti-Ro/anti-La), also rheumatoid factor
Mixed Connective Tissue Disease = U1 RNP
What is Sjogren syndrome and its two forms? What is the secondary form commonly associated with?
Chronic autoimmune disorder of lacrimal and salivary glands, common in middle-aged women
Primary - sicca syndrome (dry eyes / mouth)
Secondary - associated with another immune disease -> especially rheumatoid arthritis
What are the early and late manifestations of Sjogren syndrome in lacrimal / salivary glands?
Early - lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia
Late - Glandular fibrosis / atrophy
What is diffuse systemic sclerosis? What antibody is associated?
Rapidly progressing variant with widespread skin involvement and rapid progression / early visceral involvement.
Anti-Scl-70 antibody is associated (anti-DNA Topoisomerase 1)
What is limited systemic sclerosis? What is CREST syndrome?
Slowly progressing variant, confined to skin of face / distal upper extremities
-> does not extensively involve visceral organs
Crest - A subset of limited systemic sclerosis, characterized by:
Calcinosis Raynaud phenomenon Esophageal dysmotility Sclerodactyly Telangectasia
How does microvascular damage contribute to worsening of systemic sclerosis?
Increases platelet activation, release of growth factors for fibroblasts -> excessive collagen production
Over time, fibrinoid necrosis w/ vessel narrowing can result in tissue ischemia, resulting in more necrosis and scarring
-> can lead to ischemic ulceration and autoamputation of distal extremities
How do T cells contribute to the pathogenesis of systemic sclerosis?
- Stimulation of B cells for ANAs
- Secretion of growth factors for fibroblasts -> excessive collagen production
- Secretion of inflammatory cytokines which lead to persistent injury of microvascular endothelium
What part of the kidney is affected in systemic sclerosis and what systemic effect can this cause?
Affects the afferent arterioles due to excessive fibroblast proliferation -> leads to stenosis of the intima
Decreased renal blood flow will lead to increased renin-angiotensin-aldosterone pathway
-> high blood pressure
What are the two most problematic manifestations of systemic sclerosis now?
- Lungs - Pulmonary interstitial fibrosis -> pulmonary hypertension
- Heart - myocardial fibrosis with possible pericarditis
What are the three primary clinical features of Mixed Connective Tissue Disease? What feature is notably not present?
- SLE characteristics - fever, cytopenias
- Systemic sclerosis characteristics - Hand swelling, Raynaud phenomenon, esophageal dysmotility, pulmonary interstitial fibrosis
- Polymyositis - inflammation of muscles
Actually minimal kidney involvement as well despite SLE / Scleroderma manifestations
anti-U1 RNP
What types of infections do B cell deficiencies predispose you to?
- Bacterial - especially encapsulated / pyogenic (S. aureus, S. pneumoniae, H. influenzae)
- Enteroviruses, (i.e. polio & coxsackie)
- Giardia lamblia
Last two need IgA
What is the most common cause of SCID? Its pattern of inheritance?
X-linked
- > due to a defect in IL-2 receptor gamma-chain.
- > deficient T cell proliferation
Why must the donor bone marrow in allogeneic stem cell transplant for SCID be depleted of mature T cells?
Can induce graft-versus-host disease
- > also a risk in blood transfusion
- > all newly developing T cells will develop in patient’s thymus and have central tolerance
What infections is a DiGeorge patient susceptible to?
All infections requiring cytotoxic or delayed hypersensitivity
->viral, fungal, and TB infections
(serum Ig levels, and antibody response to most bacteria is normal assuming there’s any T function at all)
What disorders are associated with XLA and why?
Arthritis and autoimmune diseases like lupus-like disorders (the few autoreactive B cells that make it into the periphery may become active due to defective BTK signalling (required for destroying self-reactive B-cells))
What disorders are associated with selective IgA deficiency?
Increased respiratory allergies, autoimmune diseases like RA / SLE, and Celiac disease
What is common variable immunodeficiency (CVID)? How does it differ from the other similar condition?
The common variable is “hypogammaglobulinemia”
- > group of heterogeneous disorders which decrease Ig’s sometimes only IgG, most often due to failure to form plasma cells, sometimes due to T cell dysregulation
- > differs from Bruton’s because it is autosomal recessive and not X-linked
(seen in girls now)
-> also tends to be diagnosed much later than Bruton’s, in teenage years
What finding is common in lymphoid tissue in the duodenum due to CVID? Why are non-caseating granulomas present in CVID?
Nodular lymphoid hyperplasia -> persistent antigen stimulation of B cells, but plasma cells are absent
Granulomas: Pyogenic bacteria which cannot be neutralized via antibodies must be surrounded by T-cells and macrophages
What disorders are associated with CVID, and what is the treatment?
Autoimmune disorders like RA, and B-cell lymphomas
-> treatment: periodic IV immunoglobulin (same as XLA)
What causes Wiskott-Aldroch Syndrome?
Mutation in WASp, which functions in reorganizing cytoskeletal actin.
This is required for B cell, T cell, and platelet function
Early on, what type of infection are Wiskott-Aldroch patients susceptible to? What poses their greatest risk of death?
Susceptible to encapsulated pyogenic bacterial infection (poor polysaccharide antibody response, peptide is okay)
-> Bleeding risk due to low, small platelet count risks death
With age:
Progressive depletion of lymphocytes in blood and T-cells as well -> loss of cellular immunity (was present before)
-> increased risk of lymphoma. Disease must be treated with stem cell transplant.
What causes Ataxia-Telangectasia? What is the diagnostic quad of ataxia-telangectasia?
Autosomal recessive defect in ATM gene
-> unable to repair double-strand DNA breaks
4 A’s
Cerebellar Ataxia
spider Angiomas (telangectasia)
IgA deficiency -> sinopulmonary infections
elevated Alpha-fetoprotein (impaired organ development)
What causes LAD-1?
CD18 defect, an integrin, required for phagocyte adhesion, migration, and chemotaxis
Autosomal recessive
What are the clinical manifestations of Leukocyte Adhesion Deficiency (LAD-1)?
Recurrent skin / mucosal bacterial / fungal infections, lack of pus formation (neutrophils cannot migrate out), leukocytosis from high neutrophils in the blood, impaired wound healing, and periodontal disease
What are bare lymphocyte syndrome types II and III a subset of, and what causes them?
Subset of autosomal recessive SCID
-> caused by a deficiency in Class II MHC molecules, and markedly impaired cellular and humoral immunity, predisposing to all infections.
How are lesions in chronic granulomatous disease histologically unique?
Central core of neutrophils surrounded by a T-cell / macrophage lymphoma
-> can’t kill the bacteria via ROS, but can surround and contain the infection in granulomas of subcutaneous tissue
What are two tests for diagnosis of CGD?
- Dihydrorhodamine (DHR) flow cytometry test -> CGD neutrophils can’t oxidize DHR to fluoresce rhodamine
- Nitroblue tetrazolium (NBT) -> CGD neutrophils can’t turn yellow NBT to insoluble, black NBT
Treatment: gamma-interferon (make neutrophils better at using the non-oxidative pathway)
What happens to granular cells in (autosomal recessive) Chediak-Higashi?
They have giant granules due to fusion of cytoplasmic granules (defective lysosomes)
-> will lead to neutrophil phagocytosis dysfunction
What happens to the skin in CH?
Giant melanosomes in melanocytes -> partial albinism due to poor spreading of melanin
How is the nervous system affected in CH? Platelets?
Progressive dysfunction and peripheral neuropath, not well understood (likely microtubule dysfunction)
Platelets - mild coagulation deficiency due to dense body problem
What are “skip” metastases?
Skipping metastasis to the first lymph node due to alteration in normal drainage (usually due to surgery or radiation)
What types of tumors spread via hematogenous spread? Do they enter venous or arterial circulation?
Carcinomas -> after lymph nodes
Sarcomas -> directly from mesenchymal cells (do not typically go to lymph nodes first)
Typically enter venous circulation first since walls are thinner
Where do the tumors typically spread in hematogenous involvement? State where colon cancer, breast cancer, renal cancer, osteosarcoma, and prostate cancer tends to spread to.
Via wherever the venous drainage goes to, seeding multiple little cancerous nodules
For example:
Colon cancer / Pancreatic cancer -> spread to liver via portal system
Breast cancer, renal cell carcinoma, osteosarcoma -> spread to lungs via systemic circulation
Prostate cancer -> spreads to vertebral bodies via paravertebral plexus
What is a mixed tumor? Give an example.
Neoplasm showing differentiation towards more than one cell type
-> fibroadenoma of the breast, would contain both fibrous connective tissue and glandular tissue
What are some common alterations in function which can occur with loss of differentiation?
- Loss of normal function
- Acquisition of atypical function
-> Aberrant hormone synthesis
parathyroid hormone in squamous cell carcinoma of lung, gastrin in islet cell tumors of pancreas
or
-> synthesis of fetal proteins
AFP in hepatocellular carcinoma
What are the clinical features seen in tumors which seed body cavities?
- Collection of fluid -> ascites, pleural effusion, hydrocephalus, etc due to angiogenesis of tumor
- Accumulation of mucinous material -> for mucous-secreting tumors
What do malignancies do to the overall metabolic status of the patient?
They cause cachexia -> cytokines produced by macrophages &/or tumor cells = TNF, IL-1 -> decrease appetite and increase fat and muscle metabolism.
This leads to a wasting syndrome
What is a paraneoplastic syndrome?
Symptoms occurring in some patients with malignancies which cannot be accounted for by tumor growth / spread or endogenous hormone synthesis of the tissue
What is an endocrinopathy and give a few examples? What cancer type is notorious for this?
A paraneoplastic syndrome due to the producton of an ectopic hormone or hormone-like substance by a tumor of origin which shouldn’t have made it.
I.e. cushing syndrome in small cell lung cancer due to ACTH synthesis
ADH secretion in small cell lung cancer
Hypercalcemia due to PTH synthesis of squamous cell lung cancer
What cancers tend to seed entire body cavities with cancer?
Ovarian cancer -> peritoneal cavity
Lung cancer -> pleural cavity
Breast cancer -> mediastinum
Medullablastoma -> subarachnoid space
Little cancers all over the surface
What is polycythemia? Carcinoid syndrome?
Increased red blood cell mass in blood due to ectopic eythropoietin synthesis (normally made by interstitial cells of kidney, now renal cell carcinoma)
-> poly-cyte-hemia = many blood cells
carcinoid syndrome = serotonin syndrome from serotonin release
Where do the tumors typically spread in hematogenous involvement? State where colon cancer, breast cancer, renal cancer, osteosarcoma, and prostate cancer tends to spread to.
Via wherever the venous drainage goes to, seeding multiple little cancerous nodules
For example:
Colon cancer / Pancreatic cancer -> spread to liver via portal system
Breast cancer, renal cell carcinoma, osteosarcoma -> spread to lungs via systemic circulation
Prostate cancer -> spreads to vertebral bodies via paravertebral plexus
Give a dermatologic disorder which is a paraneoplastic syndrome? Neuromyopathy?
Acanthosis nigricans -> metabolic syndrome of malignancy
Neuromyopathy -> myasthenia syndrome
What is hypertrophic osteoarthropathy?
Periosteal bone formation in distal long bones which causes arthritis, as well as clubbing of finger tips, a paraneoplastic syndrome
What are some examples in which cancer can cause hypercoagulability paraneoplastic syndromes? Why does this happen?
Some cancers can secrete pro-coagulants
- Migratory thrombophlebitis
- Nonbacterial thrombotic endocarditis (NBTE)
- Disseminated intravascular coagulation (DIC)
What type of gene is the APC gene and how does it predispose to cancer?
Tumor suppressor gene
APC normally binds onto Beta-catenin, a protein associated with E-cadherin, inhibiting B-catenin from pushing colon epithelial cells thru the cell cycle.
APC dissociates whenever WNT growth signal comes in. If APC is mutated, it will dissociate even in the absence of WNT -> APC mutations are the drivers for most colon carcinomas
Are tumor suppressor genes protooncogenes? Why or why not?
No -> when a mutation occurs, their increased activation / overexpression is not pro-growth (gain-of-function).
You need “two hits” to knock out their function and lead to uncontrolled cell growth -> recessive
What are the steps by which cancer cells invade the ECM? Does it depend solely on them?
No - it also depends on inducible characteristics of the surrounding stroma
- Detachment of malignant cells -> loss of adhesion via E-cadherin
- Enzymatic degradation of ECM -> collagenases to Type 4 collagen
- Tumor cell attachment to ECM -> via laminin / fibronectin
- Migration and invasion into ECM
How does enzymatic degradation of the ECM occur? What will this cause?
Malignant cells secrete proteases, and surrounding stroma / inflammatory cells will also release proteases.
This causes release of angiogenic, chemotactic, and growth factors which are normally sequestered in the ECM
How is defective mismatch repair identified? Give an example.
Via the presence of DNA microsatellite instability -> change in number of short, repeated sequences of DNA
-> Can cause frameshift mutations if not in multiples of three and lead to cancer
Example: hereditary nonpolyposis colon carcinoma (HNPCC) -> familial cancers of colon, especially cecum and right colon
How do tumor cells form circulating tumor emboli?
They adhere to eachother, than adhere to platelets via heterotypic adhesions, and can even activate the coagulation cascade to get fibrin to coat them as they embolize to distant tissues
What type of DNA repair abnormality causes xeroderma pigmentosum, and what characterizes this condition?
Defective nucleotide excision repair
-> inability to correct pyrimidine cross-linked (i.e. thymidine dimers) caused by UV radiation
Condition characterized by extreme sensitivity to sunlight with increased in sunburns, freckling, and skin cancers
What is chromothripsis?
Chromosome shattering -> a DNA alteration with multiple chromosomal breaks with loss of some chromosome segments, causing cancer
-> one massive event
What are the two events involved in chemical carcinogenesis? What order must they occur in?
- Initation - irreversible damage to DNA which cannot be repaired
- Promotion - temporary induction of cellular proliferation
Exposure to initiator must occur before exposure to promoter, and neither exposure alone can induce carcinogenesis.
Repeated replications under these conditions increase chance of further mutagenesis
Give two general examples of promoters.
- Exogenous - i.e. viral infections
2. Endogenous - i.e. hormone-induced (estrogen -> endometrial hyperplasia -> endometrial adenocarcinoma)
What are the two types of initiators and which is more common?
- Direct-acting carcinogens -> i.e. alkylating agents like nitrogen mustard, require no metabolic conversion to become carcinogenic
- Indirect-acting initiators (procarcinogens) -> require metabolic transformation to ultimate carcinogens. i.e. benzo[a]pyrene in cigarette smoke, beta-Naphthylamine for bladder cancer in aniline dye
- > under control of liver enzyme polymorphisms (genetic)
What does the field effect basically assert?
Because of the broad area of exposure to carcinogens, the presence of one malignant lesion predisposes you to having more malignant lesions in the future.
-> like a farming spreading his seeds of carcinogens and causing dysplasia all across the land
What two characteristics of dysplasia are proportion to its chance of developing into cancer?
- Degree of dysplasia -> more severe = more likely
2. Extent of dysplasia -> more premalignant lesions = more likely
What are the five factors which determine the likelihood of progression from dysplasia to malignancy?
- Grade and extent of dysplasia
- Intrinsic biologic features of that cancer
- Potency of carcinogenic agent (i.e. HPV virus, tobacco smoke)
- Genetic susceptibility (i.e. P53 polymorphisms, GST / DNA repair polymorphisms)
- Immune response
What are the AIDS-defining cancers?
Cervical carcinoma
non-Hodgkin lymphoma
Kaposi sarcoma
What helps you recognize an adenocarcinoma? What are some subtypes?
Differentiation is either evident at architectural levels with cells being arranged around a lumen, or cellular level by the presence of intracellular mucin.
Depending on how the glands grow:
- Micropapillary pattern - presence of intraluminal projections
- Ductal -> formation of tubules
- Lobular carcinoma -> linear arrays of cells
How do sarcomas tend to appear vs carcinomas?
Sarcomas typically have spindle cell morphology
-> cigar-shaped
Carcinomas are epithelioid
-> polygonal or round
How do lymphomas look? How do you differentiate from carcinomas?
Polygonal or round cells with high N:C ratios which grow in large, patternless, solid sheets -> accumulates in LN, bone arrow, liver, spleen, or CNS. Have no stroma.
Carcinomas are typically characterized by desmoplasia making them rock hard, which is absent in lymphomas
Give an example of how molecular tests could follow up immunohistochemistry?
Checking for upregulation of HER2 in breast cancer.
If IHC for HER2 is quantitatively borderline, can use FISH (fluoresence in situ hybridization) to test for presence of gene amplification
How is a prostate cancer comprehensive stage made?
Combination of the Gleason score (objective grading) and PSA serum level, as well as the anatomic (TNM score). The grading and PSA serum level have a massive effect on prognostic staging in organ-confined disease.
How are adenocarcinomas graded? Do these grades have an impact on tumor stage?
The extent of glandular formation
Yes -> certain cancers deemed anaplastic have a far worse prognosis (i.e. thyroid cancer, regardless of size) and will influence tumor stage
What are the two types of intrauterine growth retardation? When in the pregnancy do these onset?
Type 1: Symmetric Growth Retardation - early onset in pregnancy. Body and organs, including the brain, are proportionate.
-> caused by fetal conditions, i.e. early TORCH, congenital anomalies, chromosomal abnormalities
Type 2: Asymmetric Growth Retardation - late onset in pregnancy. Body and organs are disproportionately small relative to the brain.
-> caused by maternal conditions, i.e. vascular insufficiency, nutrition, toxin / drug, late TORCH infection, multiple gestations
What is meant by intrauterine growth retardation?
Being born small for gestational age, i.e. fetal growth retardation. Includes weight, height, and head circumference <10th percentile
-> Infants are born at <2500gm and are simply small despite making it to full gestation based on number of weeks
Define the following clinical categories of abortion: threatened, inevitable, incomplete, missed, recurrent.
Threatened: Blood discharge without cervical dilation
Inevitable: Prolonged bleeding with cervical dilation
Incomplete: Retention in the uterus of portions of conceptus (fetus or placenta)
Missed: Retention of dead fetus in uterus for >4 weeks
Recurrent: 3 or more consecutive spontaneous abortions
What is the definition of stillbirth and its two types?
Death prior to delivery of a potentially viable fetus (>22 weeks)
- Intrauterine death - occurring more than 24 hours prior to delivery
- > macerated stillborn - Intrapartum death - occurring within 24 hours before or during or 24 hours after delivery
- > fresh stillborn, meconium / fetal distress
What are the three basic mechanisms by which hydrops fetalis can be caused?
- Increased capillary / venous pressure
- > i.e. anemia in Rh incompatibility / ABO incompatibility (esp. Type A babies) leading to heart failure - Decreased oncotic pressure
- > i.e. loss of albumin synthesis or increased loss of albumin (renal) - Decreased capillary integrity
- > i.e. sepsis, toxins/drugs, hypoxia leading to endothelial breakdown
(basically all the causes of transudative / exudative edema)
How will the bone marrow, liver, and spleen respond to hydrops fetalis?
Bone marrow - hyperplasia of erythroid precursors to make more RBCs
Liver - extramedullary hematopoiesis + hepatomegaly
Spleen - extramedullary hematopoiesis + splenomegaly
What is the most serious long-term threat of sequelae in hydrops fetalis?
Permanent CNS damage due to hyperbilirubinemia -> easily cross BBB in fetus -> kernicterus, causing selective necrosis of neurons
-> especially thalamus and basal ganglia
What are the maternal causes of spontaneous abortion / stillbirth? Specify:
- Maternal age
- Infections
- Uterine abnormalities
- Maternal diseases
- Nutrition status
- Exposure to toxins / drugs
- Maternal age - increased risk in young or old mothers
- Infections - Commonly ascending genital infections like Mycoplasma hominis, Chlamydia, TORCH
- Uterine abnormalities - IUD, uterine alformations
- Maternal diseases - HTN, diabetes vascular insufficiency, antibodies from previous pregnancy
- Nutrition status - decreased folate, zinc
- Exposure to toxins / drugs - cigarettes, teratogens
This, along with fetal causes is shared with causes of IUGR.
Only difference is obstetrical difficulties can cause intrapartum stillbirth (i.e. traumatic birth injury / asphyxia).
Define the following traumatic birth injuries:
Cephalhematoma: hemorrhage under the periosteum of the skull which can lead to the thickening of the skull
Caput succedaneum: Interstitial fluid in soft tissues of the scalp - not clinically significant
Intracranial hemorrhage: Most common IMPORTANT birth injury
Osteodiathesis: Separation of cranial bone sutures, happens especially with occipital sutures
What are some specific patterns of acute organ injury due to asphyxia?
- Hypoxic-ischemic brain damage -> especially in Purkinje cells
- Neonatal respiratory distress syndrome
- Acute tubular necrosis in kidneys
- Lymphocyte depletion in thymus (starry sky appearance)
- Adrenal hemorrhages
How is maturity of the lungs measured in utero?
Lecithin:sphingomyelin ratio in amniotic fluid. If >2, very low chance of neonatal respiratory distress syndrome. (Lecithin is produced more later, and sphingomyelin gets filtered out)
-> Type 2 pneumocytes start producing DPPC / Lecithin by 22 weeks, fully matured by 36 weeks.
Corresponds to end of canalicular period and beginning of alveolar sac period
What is being assessed on APGAR score and what is the highest score possible? List the best possible state in each category
APGAR
Appearance - Completely pink (vs blue body, or blue extremities)
Pulse - >100 bpm
Grimace - Cough / Sneeze to nasal catheter
Activity - Active motion (vs just some flexion)
Respirations - Good / crying is best
All scores are 0, 1, or 2
Highest score is 10, >7 is normal, <3 = poor prognosis
NOTE: prematurity = birth before 37 weeks
What is bronchopulmonary dysplasia? What pathologically characterizes it?
The condition which develops if the infant (<32 weeks) survives RDS with >28 days of oxygen.
Characterized by alveolar interstitial fibrosis (lots of scarring), and obliteration of airspaces with hyperplasia and squamous metaplasia of the bronchiolar epithelium (in the bronchi / bronchioles). Often, the alveoli will be lined by Type 2 pneumocytes which are cuboidal since they can divide and Type 1 can’t.
What is associated with the development of intracerebral hemorrhage, and how are these graded?
RDS -> small vessels will supply this embryonic area and hemorrhage when there is hypoxia (due to damage).
Graded 1-4 based on where hemorrhage spreads
1 = confined to germinal matrix 2 = extension into lateral ventricle without dilation 3 = Intraventricular hematoma with dilatation 4 = Extension back into parenchyma of brain
What is the pathogenesis of necrotizing enterocolitis?
Ischemic damage due to generalized hypoperfusion of gut when shuttling blood towards more vital organs during RDS.
Injury allows to transluminal migration of gut bacteria, followed by inflammation and necrosis of gut wall, with perforation, peritonitis, sepsis, and shock
What does necrotizing entercolitis look like pathologically (where does it happen)? What is the special name for one of these features?
Typically in terminal ileum or right side of colon, intestine shows dilatation / segmental necrosis, air bubbles in wall (pneumatosis intestinalis) -> due to bacteria and poor integrity of luminal epithelium which was never perfused in the past due to feeding via central line, and often perforation.
What is the medical definition of SIDS? Is it common?
Sudden death of an infant between week 3 and 8 months, apparently during sleep, not preceded by signs and symptoms of a lethal disease
Still the leading cause of death in infants age 1 month to 1 year in USA (most will happen by 6 months)
What is the most likely pathogenesis of SIDS?
Delayed development in brain arousal / cardiorespiratory centers, involving serotonin pathways in medulla.
-> spontaneously stop breathing
Why are neonates so susceptible to infection?
Immature liver, bone marrow, and spleen disallows speedy compensatory WBC and RBC synthesis
-> immune system not fully developed til 1 year
Brain is also immature, leading to poor hemodynamic and thermal control
-> shock and hypothermia if stressed
What are the internal pathologic findings of SIDS?
Congested lungs
- Petechiae on pleura, thymus, and epicardium
- Thymic involution (like in asphyxia of abortion / stillbirth)
- URI evidence not sufficient enough for death
- Gliosis (glial scarring) and CNS changes
How does Parvovirus B19 or “fifth disease” / erythema infectiosum appear in a bone marrow smear? What will this cause clinically?
With intranuclear viral inclusions in the bone marrow of erythroid cells -> leads to congenital anemia / hemolysis.
-> Hemolysis leads to hydrops fetalis from anemia. May lead to abortion / stillbirth
This and Syphilis are given “other” in TORCH
Note: HIV, Hep B, Zika, and Listeria are also transplacental. First two most likely to do maternal to fetal transfusion across placenta, even during birth.
What is the ascending, amniotic route of infection? When does this occur?
Transcervical, occurs in utero or around time of birth -> organisms penetrate ruptured membranes and invade amniotic fluid, which fetus may inhale before birth or during delivery
How does postnatal examination of placenta help identify infection?
Chorioamnionitis - inflammation of chorion and amnion of placenta
Funisitis - inflammation of umbilical cord
-> often candida or HSV
What is it called when you transmit infection during passage through the birth canal? What are a few common culprits?
Intrapartum route
Commonly:
Gonorrhea, Chlamydia, HSV, Group B strep, E. coli K1, Listeria, VZV, S. aureus
What is the most common congenital tumor? Why can they be a problem?
Hemangioma - a tumor of mature blood vessels
-> may lead to high output cardiac failure
Other common pediatric conditions: heterotopias / choristomas, hamartomas (especially lung)
What syndrome is associated with the development of multiple hemangiomas in the retina, brain, and other organs? Mode of inheritance?
von Hippel-Lindau -> think of the lady with cysts all over her
Autosomal dominant
What would be considered early vs late onset perinatal infection? Most common organism?
Early - within first 7 days
Late - 7 days to 3 months
Most common organism is Group B Streptococcus
What is Letterer-Siwe disease? Prognosis?
The most severe form of Langerhans cell histiocytosis
- > Acute disseminated
- > Skin / systemic involvement, onset in infancy with rapid progression
What is Hand-Schuller-Christian disease? When is the onset / prognosis
Langerhans cell histiocytosis with multifocal lesions
- > typically involves bones / organs
- > onset is childhood
- > many patients develop diabetes insipidus due to involvement of posterior pituitary
- > controllable by chemotherapy
Are fibromastoses dangerous? Where do they tend to develop?
Tend to develop in the skin, fingers, and neck (especially near sternocleidomastoid muscle)
Proliferation of fibroblastic cells in soft tissues
What is the solitary lesion form of langerhans cell histiocytosis called, and where and when is it identified?
Eosinophilic granuloma
- > lytic lesion within bones appearing in late childhood / early adulthood
- > excellent prognosis, heals spontaneously or by local excision
How is Langerhans cell histiocytosis identified histologically?
Langerhans cells with grooved, irregular nuclei and cytoplasmic inclusions called “Birbeck granules” -> an endosomal inclusion.
Langerhans cells are associated with EOSINOPHILS, plasma cells, and lymphocytes
What is the difference between mature and immature teratomas, what germ layers do they express, and are they ever malignant?
Mature - express adult somatic tissues
Immature - exist as differentiating embryonal / fetal tissues
- > both types will express all three germ layers
- > only immature teratomas in adults will be malignant
What is the definition of deformation?
Morphological defect of an organ or structure arising from an EXTRINSICALLY abnormal developmental process
-> i.e. physical stress caused by mechanical forces, like oligohydramnios leading to the potter sequence
Give a brief description of the Potter sequence?
Oligohydramnios due to renal agenesis, amniotic leak, or other causes starts a sequence
- > fetal compression leads to flattened face, positioning defects of hand / feet, and breech position (unable to turn in utero)
- > pulmonary hypoplasia due to lack of amniotic fluid to drink for developing lung
What is a syndrome (in development)?
Multiple anomalies thought to be pathophysiologically related but cannot be explained on the basis of a single initiating defect -> includes viral infection (i.e. rubella) or chromosomal abnormality (i.e. NF-1, with neurofibromas, cafe au lait spots, and lisch nodules)
How does an association differ from a syndrome?
Association - multiple anomalies which are STATISTICALLY related, but not known to share the same timing in embryology, or origin
Give an example of an association?
VATER Vertebral anomalies Anal atresia Tracheo- Esophageal fistula Radial dysplasia / Renal abnormalities
What is a developmental field defect?
Multiple anomalies resulting from a single disturbed development of a morphogenic region of the embryo
-> i.e. caudal regression syndrome (agenesis of caudal axis, including bladder, anus, genitalia, and lower extremities)
What are the four types of glycosphingolipids? Give the base, one sugar, with sulfates added, and with sialic acid added? Begin by saying what the backbone / functional groups are.
Backbone = sphingosine
C-C-N of serine, C2 will hold all the sugars.
Ceramide: C1 has palmitate, N has N-acetylated fatty acid
Cerebrosides: One sugar at C2, either glucose or galactose (i.e. glucocerebroside)
Sulfatides: Sulfate group attached to galactocerebroside
Globoside: Neutral, with extra sugars added to C2
Ganglioside: Includes sialic acid residues, which are charged (O or N-acetylneuraminic acid)
What are the clinical features shared by mucopolysaccharidoses?
- Organomegaly
- Abnormal facies
- Joint stiffness and deformity
- Cognitive impairment
What enzyme is deficient in Hunter syndrome and what accumulates in urine?
Iduronate sulfatase -> need to take sulfate groups off uronic acid sugars before they can be cleaved by alpha-iduronidase
Same accumulation as Hurler: heparan and dermatan sulfate
What are the two broad Types of Niemann-Pick disease and what causes it? Which group is overall most common?
Type I - Deficiency in spingomyelinase -> accumulation of sphingomyelin in reticuloendothelial system, among others
Type II - Defect in cholesterol esterification (NPC1 / NPC2), leading to lysosomal accumulation of unesterified cholesterol.
-> more common overall
What are the two subtypes of Type I Niemann-Pick (sphingomyelinase deficiency)? Give the clinical features overall, and the one thing that really distinguished type A from Type B.
- Type A - “severe infantile”, more common.
- > neurodegeneration (vacuolization / ballooning of neurons), hepatosplenomegaly, lipid-laden macrophages, “cherry-red” spot on macula like Tay-Sachs. - Type B - “chronic visceral”
- > organomegaly but NO CNS INVOLVEMENT
What are the GM2 gangliosidoses? Why are the clinically similar? What enzymes are messed up?
Tay-Sachs disease - alpha-subunit of hexaminidase A
Sandhoff disease - beta-subunit of hexaminidase A
Activator deficiency - GM2 activator
All lead to accumulation of GM2
What enzyme is deficient in Metachromatic leukodystrophy and what will accumulate?
Arylsulfatase A - galactocerebroside sulfate will accumulate in Schwann cells / oligodendrocytes (a major component of myelin membranes)
What enzyme is defective in Fabry disease and what substrate accumulates?
alpha-galactosidase A
-> accumulates Gb3 or ceramide trihexose
What are the major clinical features of classic galactosemia?
Liver problems: hepatomegaly
CNS problems: failure to thrive and intellectual disability
Eye problems: Cataracts within a few days (accumulation of galactitol, toxic substance)
** Infection susceptibility: E. coli sepsis in neonates
GaLaCtOsEmIa
What are the pathologic findings of galactosemia?
Steatosis of hepatocytes w/eventual cirrhosis
-> explains hepatomegaly
Brain: edema, gliosis, neuronal necrosis
-> explains intellectual disability
What are two non-classical forms of galactosemia?
- Galactokinase deficiency (can’t attach 1-phosphate to galactose for processing by uridyl-transferase)
- UDP-gal-4-epimerase (can’t convert galactose to glucose)
What type of GSD is von Gierke disease and what enzyme is absent?
von Gierke disease = Glucose-6-phosphatase, can’t do that last step in breaking down glycogen to glucose so it accumulates in sites of glycogen storage (cannot be let out into the blood as free glucose)
- > if G6P were accumulating in skeletal muscles, would just be used for glycolysis
- > this is a HEPATIC form
What are the clinical features of von Gierke disease?
Hepatomegaly and renomegaly (from glycogen accumulation)
Severe fasting hypoglycemia
Increased blood lactate -> glucose accumulates and is pushed to lactate
Marked lipidemia / ketosis, can cause eruptive xanthomas in face and buttocks -> doll-like appearance from fat deposits
What is the triad of early symptoms to remember as early manifestations of Fabry disease?
- Angiokeratomas - spotty skin lesions (red, punctate) due to dilation of capillaries
- Hypohidrosis - decreased sweating ability
- Acroparesthesia - peripheral neuropathy causing pain in hands / feet
How can Anderson and Pompe disease be clinically distinguished?
Anderson’s disease will have accumulation of abnormal glycogen -> cannot be broken down by diastase
What three deficiencies can cause PKU?
Types:
1. Phenylalanine hydroxylase (converts phenyalanine to tyrosine)
- Tetrahydrobiopterin (BH4) -> cofactor for PAH
- Dihydropteridine reductase (re-reduces BH2 to BH4 following PAH activity)
Why are the second and third types of PKU called malignant PKU?
Because they lack BH4 or BH4 reduction, which is also required to metabolize tyrosine and tryptophan
-> high tyrosine and low phenylalanine diet will not save them
What are the clinical features of PKU and why?
Severe intellectual disability, seizures, eczema, fair skin and hair color. This is because Tyrosine is needed to make T3/T4, NE / E / Dopamine, and melanin pigment
What are the functions of CFTR in lungs, GI tract, and sweat glands?
Lungs / GI tract: ATP-gated Cl- channel which secretes Cl- into lumen.
If absent: extra sodium and water are drawn in, and luminal secretions become very thick.
Sweat glands: Cl- channel normally reabsorbs Cl-. If blocked, Na+ is not reabsorbed as well, sweat becomes very high in Cl- / Na (diagnostic).
What is seen in the lungs, pancreas, intestines, and vas deferens in CF? F508 mutation in chromosome 7
Lungs - bronchial secretions are thick - recurrent respiratory infections
Pancreas - thick secretions cause blockage of ducts with pancreatic insufficiency / autodigestion of pancreas. Also leads to malnutrition
Intestines - blocked by secretions, can lead to atresia in utero as well.
Vas deferens - infertility due to thickened tube. Males commonly sterile.
What causes Marfan syndrome and what is the inheritance?
Autosomal dominant mutation in fibrillin-1 gene on chromosome 15
-> defective elastic connective tissue due to lack of glycoprotein organizing the connective tissue elastin rich in desmosine / isodesmosine linkages
Hyperextensible joints, skeletal deformities, lens dislocation, mitral valve prolapse, pectus excavatum, dilation of aorta / dissection of aorta, arachnodactyly
What protein is dysfunctional in NF-2?
Merlin - NF2 located on chromosome 22
-> tumor suppressor gene involved in communication between ECM and cytoplasm
What are the most important clinical signs of Down syndrome?
- Hypotonia (at birth) with IUGR**
- Single transverse palmar crease (only 5% chance in a normal person)
- Oblique palpebral fissues
- Clinodactyly - short, curved 5th finger
- Intellectual disability
- Hearing and heart defects
What is the mneumonic for Patau syndrome? What trisomy is it?
Patau = Trisomy 13 = Puberty
6 P’s:
- cleft Palate / lip
- holoProsencephaly
- Polydactyly
- cutis aPlasia - missing skin on scalp
- Polycystic kidney
- microPhthalmia w/ possible proboscis (due to holoprosencephaly)
What is the mneumonic for Edward syndrome?
PRINCE Edward (trisomy 18) = election age
P = prominent occiput R = Rocker-bottom feet I = intellectual disability N = nondisjunction C = Clenched fists (overlapping fingers) E = Low-set ears
Remember also microcephaly with micrognathia and congenital heart disease
What gonadal and cardiac defects are common in turner syndrome?
Gonadal - ovarian dysgenesis (streak gonads / made of fibrous tissue)
Cardiac - coarctation of the aorta (narrowing, around ligamentum arteriosum)
What pre-mutation state of Fragile X affects males mostly? How is it detected?
Fragile X Tremor Ataxia Syndrome (FXTAS) - late onset, progressive cerebellar ataxia and intention tremor affecting males
Detected via white matter lesions to middle cerebellar peduncles on MRI
What is MERRF? How is it clinically identified? Via the lab?
Myoclonic Epilepsy associated with Ragged Red Fibers
Myoclonus, seizures, cerebellar ataxia, and lactic acidosis
Ragged red fibers on muscle biopsy due to replication of mitochondria in an attempt to compensate (seen with trichrome stain)
Succinate dehydrogenase stains highlight the extra mitochondria (complex 2 encoded by nuclear enzymes)
Subsarcolemmal mitochondria with paracrystalline inclusions by EM
What are the clinical features of Prader-Willi syndrome?
Hypotonia at birth (extreme)
Intellectual disability
Obesity due to hyperphagia
Hypogonadism
Looks like Klinefelter’s + hypotonia of Down syndrome
What are the clinical features of Angelman syndrome?
Inappropriate laughter “happy puppets” -> puppets because you have to hold them up
Seizures
Gait ataxia (child needing to be held up)
Severe speech impairment / intellectual disability
What are the clinical manifestations of CJD?
Rapidly progressive dementia and prominent startle myoclonus (clapping will make the patient shake)
What are the microscopic features of active VZV infection, and how does it differ from HSV?
Intraepithelial vesicles (blisters) with multinucleated epithelial (keratinocytes) cells with ground-glass chromatin around the periphery. Intranuclear inclusions are eosinophilic, with no cytoplasmic inclusions.
These look exactly the same as HSV under the microscope because VZV is a herpesvirus.
What does CMV look like pathologically? Make sure to contrast this with VZV.
“Owl’s eye” - according to sketchy
Enlarged, basophilic intranuclear inclusion sourrounded by a halo and (unlike VZV) multiple, smaller, basophilic intraCYTOPLASMIC inclusions.
-> nuclei do not tend to aggregate together like VZV
What is the most common manifestation of HPV called and where does it appear? Microscopically?
Verruca vulgaris - common wart
Appears as small, pale papules with a roughened surface, often on dorsum of hands or soles of feet.
- > major thickening of squamous epithelium (mitosis is induced by virus)
- > thick keratin makes the warts appear white
How does gas gangrene look under the microscope?
Like coagulative necrosis with large vacuoles -> gas bubbles, death of immune cells which try to fight the infection
How does syphilis infection look pathologically? What feature of tertiary syphilis does this explain?
- Many plasma cells nearby trying to clear the infection (nonspecific antibodies generated which are picked up by VDRL test, reacting with beef cardiolipin)
- Obliterative endarteritis -
vascular pathology causes compression of blood vessels
-> explains death of vasa vasorum leading to thoracic aortic aneurysm in tertiary syphilis
What is the micropathology of gummas?
Granulomatous inflammation surrounding the treponema
What one feature would make you suspect ophthalmia neonatorum is due to Chlamydia and not gonorrhea (other than time of onset)?
Often associated with infant pneumonia (staccato cough)
-> can infect the PSCC (along with transitional epithelium)
What cell type does Rickettsia rickettsii have tropism towards? When should its primary infection be treated?
Tropism towards vascular endothelial cells -> causes vasculitis
-> Rocky Mountain Spotted Fever is potentially life threatening, treatment with doxycycline should not be delayed if you think it is possible
What are the clinical features of RMSF? What type of rash is it?
Fever and headache early on, followed by a rash with centripetal spread (spread from extremities towards the trunk)
- > will include palms and soles
- > Rash is a petechial rash which is nonblanching due to bleeding into the dermis
- > thrombocytopenia is caused by clotting forming around vasculitis areas
What type of skin lesions exist in the paucibacillary form of leprosy, and what will be seen pathologically? What is the other name for this form?
Tuberculoid - paucibacillary just means few bacilli since the infection is well-controlled by Th1 immune response
Pathology - many well-formed granulomas
Skin - hypopigmented, hypoesthetic (damage to peripheral nerves)
What type of skin lesions exist in the multibacillary form of leprosy, and what will be seen pathologically? What is the other name for this form?
Lepromatous- there will be many bacilli in the skin lesions since the infection is poorly-controlled by a Th2 immune response
Pathology - Sheets of foamy macrophages containing bacilli, which will also be present in endothelial and Schwann cells
Skin - larger, deep, more destructive skin lesions, with saddle-nose and lion-like faces
What are the early findings of blastomycosis? What are the skin findings of blastomycosis? Who tends to get this?
Early neutrophilic infiltration, followed by chronic granulomatous inflammation. Chronic pneumonia will have systemic symptoms (due to granuloma cytokines)
Small papules and pustules which can enlarge to ulcerated plaques with scarring
- > can later spread to bones
- > generally immunocompromised
What are the two forms of aspergillosis which ARE associated with being immunocompromised? What defect makes you susceptible?
Especially neutropenia
- Chronic necrotizing Aspergillus pneumonia - chronic lung disease
- Angioinvasive aspergillosis - causes thrombotic / hemorrhagic complications by invading vessels with acute angle hyphae, with dissemination to extrapulmonary organs and ring-enhancing lesions on CT.
What patients are most susceptible to zygomycetes infection and how does the pathogen like to invade?
Neutropenic patients (i.e. leukemia) and uncontrolled diabetic ketoacidosis (high glucose environment which allowed molds to survive)
Pathogen invades vascular tissue first, causing hemorrhage, thrombosis, and infarction
What is the life cycle of Trypanosoma cruzi / how is it spread to humans? What cells do they replicate in?
Epimastigotes in insets replicate, before becoming trypomastigote which is infectious.
Triatomine / kissing bug will bite around the human’s face and night then poop in the trypomastigotes into the wound. These can circulate in the bloodstream and replicate intracellularly as the amastigote form (within CARDIAC and SMOOTH muscle cells)
What is the life cycle of Schistosoma, including where they diverge between the two subtypes? What is their intermediate host
Snails are intermediate host, release cercariae into water which penetrate human skin, then disseminate to portal circulation hematogenously.
- > Hepatic / intestinal will migrate as a pair to mesenteric veins
- > Urinary will migrate to vesicular veins
- > eggs are released in stool or urine respectively, which are taken up by snails after hatching
What does early infection with Schistosoma cause?
Swimmer’s itch -> pruritic or papular rash where cercariae penetrated
Still in early stage: lymphadenopathy, hepatosplenomegaly, and reactive eosinophilia
-> may be subclinical
What will be the late complications of the hepatic / intestinal forms of schistosomiasis (months to years later)?
Abdominal pain / bloody diarrhea, with development of intestinal obstruction / hepatic periportal “pipestem” fibrosis due to granulomatous inflammation
-> portal hypertension and associated symptoms are likely
What are the symptoms of the three phases of Trichinella infection if the inoculum is heavy?
- Enteral phase (week one) -> vomiting, diarrhea, nausea, hemorrhage, ulceration
- Parental / migratory phase (past 1 week) -> eosinophilia, periorbital edema, systemic symptoms. Muscle swelling / pain as they encyst, can even cause elevated muscle enzymes
- Encystation phase with tissue repair -> larvae become surrounded by fibrosis and skeletal muscle as cyst wall calcifies, with resolution of clinical symptoms.
- > multinucleated skeletal muscle cells which surround the encysted larve
