Autoimmune & Immunology Flashcards
Question
E. Soluble receptor decoy protein
Etanercept is a tumor necrosis factor-alpha (TNF-α) inhibitor added to methotrexate to treat moderate-to- severe rheumatoid arthritis in patients who have failed methotrexate alone. It is a fusion protein linking a soluble TNF-α receptor to the Fc component of human immunoglobulin G1 (IgG1). Etanercept reduces the biological activity of TNF-α by acting as a decoy receptor: the TNF-α receptor component acts like a sponge to bind TNF-α and keep it away from functional TNF-α receptors, while the Fc component stabilizes the complex.
Pharmaceutical companies provide the prefix of the names for biological agents; the suffix indicates whether the medication is a monoclonal antibody (mab), a receptor molecule (cept), or a kinase inhibitor (nib). Monoclonal antibodies, which are the largest group of biological agents, also include in their names the type of target (eg, bacterial or immune system) and their origin (eg, human or mouse).
(Choice A) Rituximab (Ri-tu-xi-mab) is a chimeric monoclonal antibody targeted against CD20, a cell receptor found on the surface of B cells. It is used to treat CD20+ non-Hodgkin’s lymphomas and other diseases related to excessive B-cell function.
(Choice B) Infliximab (Inf-li-xi-mab) is a chimeric monoclonal antibody targeted against TNF-α. It is used in the treatment of a number of autoimmune diseases (eg, rheumatoid arthritis and Crohn’s disease).
(Choice C) Certolizumab pegol (Certo-li-zu-mab) is a pegylated (pegol) humanized monoclonal antibody that targets TNF-α. It lacks the Fc region, which helps minimizes complement activation and cell-mediated cytotoxicity that can occur with other anti-TNF-α medications that contain Fc domains.
(Choice D) Imatinib (Imati-nib) mesylate is used to treat specific cancers, including Philadelphia chromosome-positive chronic myelogenous leukemia and kit-positive gastrointestinal stromal tumors. It is an example of a small-molecule tyrosine kinase receptor inhibitor.
Educational objective:
The suffix of a biological agent indicates whether a medication is a monoclonal antibody (mab), a receptor molecule (cept), or a kinase inhibitor (nib). Monoclonal antibodies also include in their names the type of target (eg, bacterial or immune system) and their origin (eg, human or mouse).
Etanercept MOA
Etanercept is a tumor necrosis factor-alpha (TNF-α) inhibitor added to methotrexate to treat moderate-to- severe rheumatoid arthritis in patients who have failed methotrexate alone.
soluble receptor decoy
Rituximab
Question
D. Perforin
This patient’s peripheral blood smear reveals a reactive (atypical) lymphocyte. In contrast to normal lymphocytes, which are small, round, and have minimal cytoplasm, reactive lymphocytes are large, scalloped, and have abundant cytoplasm.
Reactive lymphocytes are activated, pathogen-specific cytotoxic T cells and natural killer cells that form in response to certain intracellular infections (eg, HIV, cytomegalovirus, toxoplasmosis); they are particularly linked to infectious mononucleosis, a primary Epstein-Barr virus characterized by fever, pharyngitis, adenopathy, splenomegaly, and severe fatigue (as is likely in this patient).
Reactive lymphocytes are effector cells that contain cytotoxic granules composed of perforin (creates holes in the infected cell’s membrane) and granzymes (enter the cytoplasm of infected cells and trigger cell death), which are released in response to foreign antigens on the surface (MHC class I receptors) of infected host cells.
(Choice A) Elastase breaks down collagen and is released by neutrophils and macrophages during acute inflammation. Neutrophils have multi-lobe nuclei and pinkish cytoplasm; macrophages have central round nuclei and abundant greyish, vacuolated cytoplasm. Neither typically has scalloped edges or abundant basophilic cytoplasm.
(Choice B) Immunoglobulins are secreted by plasma cells, which have an eccentric nucleus, perinuclear paleness (large Golgi apparatus), and spoke-wheel chromatin. Although immunoglobins cannot typically be visualized on light microscopy, immunoglobulin inclusions can sometimes be seen in plasma cell malignancies such as multiple myeloma (characterized by anemia, hypercalcemia, bone pain, and renal insufficiency).
(Choice C) Eosinophils generate and release major basic protein, which is the core constituent of eosinophilic granules; it acts as a cytotoxin and helminthotoxin and mediates epithelial damage, exfoliation, and bronchospasm in hypersensitivity diseases. Eosinophils have a bilobed nucleus and stain intensely pink.
(Choice E) Ribosomes generate proteins from messenger RNA; they can be visualized by electron microscopy but usually cannot be seen on light microscopy. However, ribosomal aggregates can sometimes be seen as basophilic stippling in patients with thalassemia or alcoholism.
(Choice F) Viral capsids are usually bound to viral genomes and shed in the cytoplasm prior to viral replication. This typically cannot be seen on light microscopy. Atypical lymphocytes are not infected by virus; they react to infected cells.
Educational objective:
Reactive (atypical) lymphocytes are activated, pathogen-specific cytotoxic T cells or natural killer cells that form in response to certain intracellular infections. In contrast to normal lymphocytes, reactive lymphocytes are large, scalloped, and have abundant cytoplasm. Reactive lymphocytosis is a diagnostic feature of infectious mononucleosis.
Identify cells
What kind of cells are these?
Question
D. Small vessels damaged by perivascular neutrophil accumulation
This patient has a purpuric rash, arthralgia, and signs of renal disease (ie, hypertension, proteinuria), which are classic features of Henoch-Schönlein purpura (HSP), or IgA vasculitis. Other common findings can include colicky abdominal pain and hematuria.
HSP is an immune-mediated type III hypersensitivity reaction in which deposition of IgA immune complexes (which may form in response to a preceding upper respiratory infection) triggers complement activation and inflammation of small vessels throughout the body. Vasculitis within the papillary dermis manifests as nonthrombocytopenic palpable purpura on dependent areas, such as the buttocks and lower extremities. Histopathology shows leukocytoclastic vasculitis, in which small superficial blood vessels are damaged by perivascular neutrophilic inflammation, resulting in fibrin deposition in the vessel wall (ie, fibrinoid necrosis) and red blood cell extravasation. Neutrophil breakdown (leukocytoclasis) leads to the formation of perivascular nuclear debris. Immunofluorescence reveals IgA and C3 in the vessel walls.
HSP is usually benign and self-limiting, particularly in children. However, adults are at increased risk for renal complications, such as nephrotic syndrome and acute kidney injury.
(Choice A) Disseminated intravascular coagulation is characterized by abundant intravascular fibrin deposition (ie, fibrin thrombi) in the absence of vascular inflammation. It occurs most often in the setting of trauma, sepsis, or malignancy and presents with bleeding (eg, purpura) due to thrombocytopenia and coagulopathy. Although fibrin thrombi may be seen with HSP, extensive inflammatory infiltrate is also present.
(Choice B) Obliterative endarteritis with lymphocytes and plasma cells is seen with later-stage syphilis, which can cause arthralgias, renal abnormalities, and a rash; however, classic skin findings include scaly red/brown macules or papules that are typically diffuse and involve the palms and soles. In contrast, this patient has purpuric lesions localized to the lower extremities.
(Choice C) Perivascular necrotizing granulomas with eosinophilic infiltration are characteristic of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), a small- to medium-vessel vasculitis. It can cause renal, skin, and joint involvement later in life (eg, third to fourth decades) but initially presents with asthma symptoms, which are not seen in this patient.
(Choice E) Transmural granulomatous inflammation with fragmentation of elastic fibers is a typical finding of giant cell arteritis, seen in adults age >50. It involves medium/large arteries and most commonly presents with headache.
Educational objective:
Henoch-Schönlein purpura, or IgA vasculitis, classically presents with palpable purpura, with or without abdominal pain, arthralgias, and renal involvement. Histopathologic examination of the skin lesions reveals damaged small vessels with fibrinoid necrosis, perivascular neutrophilic inflammation, and nuclear debris (ie, leukocytoclastic vasculitis). Immunofluorescence reveals deposition of IgA and C3.
Henoch-Schönlein purpura (IgA vasculitis) histology
Histopathology shows leukocytoclastic vasculitis, in which small superficial blood vessels are damaged by perivascular neutrophilic inflammation, resulting in fibrin deposition in the vessel wall (ie, fibrinoid necrosis) and red blood cell extravasation. Neutrophil breakdown (leukocytoclasis) leads to the formation of perivascular nuclear debris. Immunofluorescence reveals IgA and C3 in the vessel walls.
Henoch-Schönlein purpura (IgA vasculitis) clinical manifestations
Palpable purpura/petechiae on the lower extremities
Arthritis/arthralgia
Abdominal pain, gastrointestinal bleeding, intussusception
Renal disease (hematuria ± proteinuria)
Henoch-Schönlein purpura pathophysiology
Deposition of IgA immune complexes in small vessels activates complement
Neutrophilic inflammation & vascular damage
Often follows an upper respiratory infection
