Atopic Dermatitis: Pathophysiology.

The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell-mediated immune responses, IgE-mediated hypersensitivity, and environmental factors. Loss-of-function mutations in filaggrin have been implicated in severe atopic dermatitis due to a potential increase in trans-epidermal water loss, pH alterations, and dehydration. Other genetic changes have also been identified, which may alter the skin's barrier function, resulting in an atopic dermatitis phenotype. The imbalance of Th2 to Th1 cytokines observed in atopic dermatitis can create alterations in the cell-mediated immune responses and can promote IgE-mediated hypersensitivity, both of which appear to play a role in the development of atopic dermatitis. One must additionally take into consideration the role of the environment on the causation of atopic dermatitis and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives. Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin's pH causing downstream changes in enzyme activity and triggering inflammation. Environmental pollutants can trigger responses from both the innate and adaptive immune pathways. This chapter will discuss the multifaceted etiology of atopic dermatitis, which will help us to elucidate potential therapeutic targets. We will also review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopic dermatitis.

Atopic Dermatitis: Pathophysiology.

The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell mediated immune responses, IgE mediated hypersensitivity, and environmental factors. Loss of function mutations in filaggrin have been implicated in severe atopic dermatitis due to a potential increase in trans-epidermal water loss, pH alterations, and dehydration. Other genetic changes have also been identified which may alter the skin's barrier function, resulting in an atopic dermatitis phenotype. The imbalance of Th2 to Th1 cytokines observed in atopic dermatitis can create alterations in the cell mediated immune responses and can promote IgE mediated hypersensitivity, both of which appear to play a role in the development of atopic dermatitis. One must additionally take into consideration the role of the environment on the causation of atopic dermatitis and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives. Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin's pH causing downstream changes in enzyme activity and triggering inflammation. Environmental pollutants can trigger responses from both the innate and adaptive immune pathways. This chapter will discuss the multifaceted etiology of atopic dermatitis which will help us to elucidate potential therapeutic targets. We will also review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopic dermatitis.

Elevated double negative T cells in pediatric autoimmunity.

PURPOSE: Autoimmune diseases are thought to be caused by a loss of self-tolerance of the immune system. One candidate marker of immune dysregulation in autoimmune disease is the presence of increased double negative T cells (DNTs) in the periphery. DNTs are characteristically elevated in autoimmune lymphoproliferative syndrome, a systemic autoimmune disease caused by defective lymphocyte apoptosis due to Fas pathway defects. DNTs have also been found in the peripheral blood of adult patients with systemic lupus erythematosus (SLE), where they may be pathogenic. DNTs in children with autoimmune disease have not been investigated. METHODS: We evaluated DNTs in pediatric patients with SLE, mixed connective tissue disease (MCTD), juvenile idiopathic arthritis (JIA), or elevated antinuclear antibody (ANA) but no systemic disease. DNTs (CD3(+)CD56(-)TCRαß(+)CD4(-)CD8(-)) from peripheral blood mononuclear cells were analyzed by flow cytometry from 54 pediatric patients including: 23 SLE, 15 JIA, 11 ANA and 5 MCTD compared to 28 healthy controls. RESULTS: Sixteen cases (29.6 %) had elevated DNTs (≥2.5 % of CD3(+)CD56(-)TCRαß(+) cells) compared to 1 (3.6 %) control. Medication usage including cytotoxic drugs and absolute lymphocyte count were not associated with DNT levels, and percentages of DNTs were stable over time. Analysis of multiple phenotypic and activation markers showed increased CD45RA expression on DNTs from patients with autoimmune disease compared to controls. CONCLUSION: DNTs are elevated in a subset of pediatric patients with autoimmune disease and additional investigations are required to determine their precise role in autoimmunity.

Gallbladder containing incisional hernia in an elderly woman.

Gallbladder herniation is a rare phenomenon with risk factors of being female, older age, and previous history of hernias. Imaging modalities can confirm the diagnosis. Cholecystectomy and hernia repair to prevent strangulation may be warranted.

Polymyositis Presenting With Nontraumatic Rhabdomyolysis and Dysphagia: A Case Report.

Idiopathic inflammatory myopathies (IIMs) are a rare, heterogeneous group of diseases with a characteristic clinical presentation consisting of muscle inflammation and weakness. They often present with accompanying extra-muscular findings, most notably in the skin, lungs, and joints. Inflammatory myopathies are also identified by their characteristic laboratory abnormalities, including a 10- to 50-fold increase in creatinine kinase, elevated liver enzymes, and characteristic electromyography and magnetic resonance imaging findings. Distinct autoimmune markers and clinical phenotypes have advanced our understanding of IIMs and have led to the recognition of 5 distinct entities, each with its unique pathophysiology, autoimmune markers, and clinical features. While autoimmune panels and muscle biopsies help clinicians distinguish one entity from the other, their sensitivity and specificity vary. Of the various inflammatory myopathies, polymyositis remains the most elusive. Often, the diagnosis is ultimately made by combining clinical findings and laboratory data. As our case report illustrates, clinicians must use this constellation of data to initiate treatment for suspected polymyositis despite negative autoimmune panels and negative muscle biopsy.

Fever of Unknown Origin Reveals a Missed Diagnosis of DiGeorge Syndrome in a 21-Year-Old Female.

DiGeorge syndrome, caused by a microdeletion of the 22q11.2 region of chromosome 22, is a relatively rare condition. This syndrome can be difficult to recognize because a constellation of symptoms show different presentations. Most individuals diagnosed with this condition are identified in early childhood. With the emergence of new screening techniques, even fewer individuals with this syndrome are missed. Prior to these screening techniques, it was uncommon for patients to be diagnosed in adulthood. As a result, many internists, who focus only on the adult population, are unlikely to recognize and diagnose DiGeorge syndrome as the patient ages merely because it is not commonly diagnosed later in life. Early recognition and management are essential for the treatment of this condition. Here, we present the case of a 21-year-old woman diagnosed with DiGeorge syndrome as an adult.

Utility of routine laboratory testing in management of chronic urticaria/angioedema.

BACKGROUND: Laboratory tests are routinely ordered to identify or rule out a cause in patients with chronic urticaria/angioedema (CUA). The results of these tests are usually within normal limits or unremarkable. OBJECTIVE: To investigate the proportion of abnormal test results in patients with CUA leading to a change in management and in outcomes of care. METHODS: Retrospective analysis of a random sample of adult patients with CUA from 2001-2009. RESULTS: Cases totaled 356: 166 with urticaria and angioedema (AE), 187 with urticaria, and 3 with only AE. Patients were predominately women (69.1%) and white (75.6%), with a mean age of 48 ± 15 years. Abnormalities were commonly seen in complete blood counts (34%) and in complete metabolic panels (9.4%). Among the 1,872 tests that were ordered, results of 319 (17%) were abnormal. Of 356 patients, 30 underwent further testing because of abnormalities in laboratory work. This represented 30 of 1,872 tests (1.60%). Only 1 patient benefited from a subsequent change in management. CONCLUSIONS: Laboratory testing in CUA patients referred for an Allergy and Immunology evaluation rarely lead to changes in management resulting in improved outcomes of care.

Biomolecular endotype factors involved in COVID-19 airway infectivity: A systematic review.

OBJECTIVES: To review the current knowledge of biomolecular factors surrounding otorhinolaryngeal illnesses and analyze their presence in COVID-19 virulence. Emphasis was placed on cytokines and vitamin D for determining susceptibility of illness. METHODS: A primary literature search of PubMed and Google Scholar for articles published between January 1, 2002 to May 31, 2020, was performed without language restrictions from May 8, 2020 to May 31, 2020. A focused second search was conducted from October 31, 2020 to November 2, 2020 for articles published between January 1, 2002 to October 31, 2020. Eligible articles were selected after evaluation of titles, abstracts, and references. A total of 45 were included in this review. RESULTS: Differing endotype classification schemes are used to determine cytokines present in chronic rhinosinusitis, asthma, and allergies. While immunologic responses and biomarkers are primary methods of differentiation, recent literature has also implicated geographic distribution of chronic rhinosinusitis patients in accounting for cytokine variations. The cytokines of interest (IL-4, IL-13, and INF-γ) present in the endotypes of these conditions may point towards protective mechanisms against COVID-19 through downregulation of the ACE2 receptor. These cytokines and Vitamin D highlight new areas of study for factors affecting SARS-CoV-2 virulence. CONCLUSIONS: Further research is needed to understand the effects of Vitamin D and the various cytokines prevalent among endotypes of nasal/pharyngeal illnesses on COVID-19 pathogenesis. Findings may point towards epidemiologic trends of SARS-CoV-2 transmission and have future therapeutic indications.

Familial cold autoinflammatory syndrome with rheumatoid arthritis.

Familial cold autoinflammatory syndrome (FCAS) is a cryopyrin-associated periodic syndrome that presents with episodic fever, skin rash, and joint pain after exposure to cold temperatures. Although the diagnosis is often singular, there are several instances of concurrent underlying autoimmune pathologies with either rheumatoid arthritis (RA) or amyloidosis. Because symptoms of the two entities overlap, it can be difficult to address a potential dual diagnosis of FCAS and an autoimmune disorder. We found seven previously reported cases of FCAS and amyloidosis and five cases of FCAS and RA and present another case of an FCAS-RA dual diagnosis.

In vitro simian virus 40 large tumor antigen expression correlates with differential immune responses following DNA immunization.

Simian virus 40 (SV40) contains an essential protein, large tumor antigen (Tag), which assists in viral replication and causes cell transformation and immortalization. Our laboratory has examined plasmid DNA, expressing SV40 Tag under two different promoters, for use in potential cancer vaccination strategies. One plasmid, pSV3-neo, failed to induce SV40 Tag antibody, produced a weak cell-mediated response, and only partial protection in murine experimental tumor challenge systems. The second plasmid, pCMV-Tag, induced antibodies to SV40 Tag, produced a robust cell-mediated response, and invoked complete tumor immunity in vivo. The induction of CD4+ and CD8+ T cell responses following plasmid DNA immunization and tumor cell challenge reflected a type 1 cytokine secretion profile. Our hypothesis for this differential immune response is that pCMV-Tag exhibits a higher level of transgene expression due to a more efficient promoter. We determined that pCMV-Tag levels of SV40 Tag mRNA and protein expression were higher when compared to pSV3-neo. A threshold amount of SV40 Tag may be required to stimulate antibody production and provide complete systemic tumor immunity.