Blog

Complement Deficiencies Result in Surrogate Pathways of Complement Activation in Novel Polygenic Lupus-like Models of Kidney Injury.

February 20, 2021 By Manish Butte

Complement Deficiencies Result in Surrogate Pathways of Complement Activation in Novel Polygenic Lupus-like Models of Kidney Injury.

J Immunol. 2020 05 15;204(10):2627-2640

Authors: Skopelja-Gardner S, Colonna L, Hermanson P, Sun X, Tanaka L, Tai J, Nguyen Y, Snyder JM, Alpers CE, Hudkins KL, Salant DJ, Peng Y, Elkon KB

Abstract
Lupus nephritis (LN) is a major contributor to morbidity and mortality in lupus patients, but the mechanisms of kidney damage remain unclear. In this study, we introduce, to our knowledge, novel models of LN designed to resemble the polygenic nature of human lupus by embodying three key genetic alterations: the Sle1 interval leading to anti-chromatin autoantibodies; Mfge8-/- , leading to defective clearance of apoptotic cells; and either C1q-/- or C3-/- , leading to low complement levels. We report that proliferative glomerulonephritis arose only in the presence of all three abnormalities (i.e., in Sle1.Mfge8 -/- C1q -/- and Sle1.Mfge8 -/- C3 -/- triple-mutant [TM] strains [C1q -/-TM and C3-/- TM, respectively]), with structural kidney changes resembling those in LN patients. Unexpectedly, both TM strains had significant increases in autoantibody titers, Ag spread, and IgG deposition in the kidneys. Despite the early complement component deficiencies, we observed assembly of the pathogenic terminal complement membrane attack complex in both TM strains. In C1q-/- TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicated that the lectin pathway likely contributed to complement activation and tissue injury in this strain. Interestingly, enhanced thrombin activation in C3-/- TM mice and reduction of kidney injury following attenuation of thrombin generation by argatroban in a serum-transfer nephrotoxic model identified thrombin as a surrogate pathway for complement activation in C3-deficient mice. These novel mouse models of human lupus inform the requirements for nephritis and provide targets for intervention.

PMID: 32238460 [PubMed – indexed for MEDLINE]

Severe combined immunodeficiency caused by inositol-trisphosphate 3-kinase B (ITPKB) deficiency.

February 20, 2021 By Manish Butte

Severe combined immunodeficiency caused by inositol-trisphosphate 3-kinase B (ITPKB) deficiency.

J Allergy Clin Immunol. 2020 06;145(6):1696-1699.e6

Authors: Almutairi A, Wallace JG, Jaber F, Alosaimi MF, Jones J, Sallam MTH, Elnagdy MH, Chou J, Sobh A, Geha RS

PMID: 31987846 [PubMed – indexed for MEDLINE]

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

February 20, 2021 By Manish Butte

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

J Allergy Clin Immunol. 2020 06;145(6):1664-1672.e10

Authors: Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, Alosaimi MF, Stafstrom K, Platt CD, Stauber T, Raz S, Tirosh I, Weiss A, Jordan MB, Krupski C, Eleftheriou D, Brogan P, Sobh A, Baz Z, Lefranc G, Irani C, Kilic SS, El-Owaidy R, Lokeshwar MR, Pimpale P, Khubchandani R, Chambers EP, Chou J, Geha RS, Nigrovic PA, Zhou Q

Abstract
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable.
OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation.
METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum.
RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function.
CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

PMID: 31945408 [PubMed – indexed for MEDLINE]

[The pathology of hereditary ovarian tumors].

February 18, 2021 By Manish Butte

[The pathology of hereditary ovarian tumors].

Ann Pathol. 2020 Apr;40(2):85-94

Authors: Pesce F, Devouassoux-Shisheboran M

Abstract
About 23% of adnexal tumors are related to a hereditary syndrome, most often hereditary breast and ovarian cancer syndrome or Lynch syndrome, responsible of epithelial tumors. However, the pathologist should be aware of rare hereditary syndromes responsible of non-epithelial ovarian tumors. Ovarian tumors associated with germline mutation of BRCA genes are essentially high-grade serous carcinomas of tubal origin, while those seen in Lynch syndrome are most often endometrioid or clear cell carcinomas. Sex-cord tumors associated with a familial predisposition are Sertoli-Leydig cell tumors in DICER syndrome and sex-cord tumors with annular tubules in Peutz-Jeghers syndrome. Small cell carcinoma of hypercalcemic type may be associated with a rhabdoid tumor predisposition syndrome 2. Finally, rare germ cell tumors have been reported related to ataxia telangiectasia. The recognition of these entities by pathologists is crucial. Even though the morphologic features pointing toward an inherited mutation may vary depending on the syndrome, the diagnosis may contribute to refer the patient for genetic counselling, modifying the management and follow-up of the patient and her family.

PMID: 32178889 [PubMed – indexed for MEDLINE]

PI Prob: A risk prediction and clinical guidance system for evaluating patients with recurrent infections.

February 17, 2021 By Manish Butte

PI Prob: A risk prediction and clinical guidance system for evaluating patients with recurrent infections.

PLoS One. 2021;16(2):e0237285

Authors: Rider NL, Cahill G, Motazedi T, Wei L, Kurian A, Noroski LM, Seeborg FO, Chinn IK, Roberts K

Abstract
BACKGROUND: Primary immunodeficiency diseases represent an expanding set of heterogeneous conditions which are difficult to recognize clinically. Diagnostic rates outside of the newborn period have not changed appreciably. This concern underscores a need for novel methods of disease detection.
OBJECTIVE: We built a Bayesian network to provide real-time risk assessment about primary immunodeficiency and to facilitate prescriptive analytics for initiating the most appropriate diagnostic work up. Our goal is to improve diagnostic rates for primary immunodeficiency and shorten time to diagnosis. We aimed to use readily available health record data and a small training dataset to prove utility in diagnosing patients with relatively rare features.
METHODS: We extracted data from the Texas Children’s Hospital electronic health record on a large population of primary immunodeficiency patients (n = 1762) and appropriately-matched set of controls (n = 1698). From the cohorts, clinically relevant prior probabilities were calculated enabling construction of a Bayesian network probabilistic model(PI Prob). Our model was constructed with clinical-immunology domain expertise, trained on a balanced cohort of 100 cases-controls and validated on an unseen balanced cohort of 150 cases-controls. Performance was measured by area under the receiver operator characteristic curve (AUROC). We also compared our network performance to classic machine learning model performance on the same dataset.
RESULTS: PI Prob was accurate in classifying immunodeficiency patients from controls (AUROC = 0.945; p<0.0001) at a risk threshold of ≥6%. Additionally, the model was 89% accurate for categorizing validation cohort members into appropriate International Union of Immunological Societies diagnostic categories. Our network outperformed 3 other machine learning models and provides superior transparency with a prescriptive output element.
CONCLUSION: Artificial intelligence methods can classify risk for primary immunodeficiency and guide management. PI Prob enables accurate, objective decision making about risk and guides the user towards the appropriate diagnostic evaluation for patients with recurrent infections. Probabilistic models can be trained with small datasets underscoring their utility for rare disease detection given appropriate domain expertise for feature selection and network construction.

PMID: 33591972 [PubMed – as supplied by publisher]

Diagnosis of primary immunodeficiencies in Peru.

February 17, 2021 By Manish Butte

Diagnosis of primary immunodeficiencies in Peru.

Curr Opin Pediatr. 2020 12;32(6):798-804

Authors: Aldave-Becerra JC, Veramendi-Espinoza LE, Rentería-Valdiviezo CA

Abstract
PURPOSE OF REVIEW: Primary immunodeficiencies (PIDs) are human inborn errors of immunity, leading to an increased susceptibility to infections, inflammatory manifestations, and malignancy. We estimate around 16 000 individuals with PIDs living in Peru who are still undiagnosed. The purpose of this review is to make a situational analysis of the diagnosis of PIDs in Peru.
RECENT FINDINGS: There is an evident underdiagnosis of PIDs in Peru. Insufficient awareness and lack of diagnostic tools can be solved partially by expanding the number and expertise of Clinical Immunologists and specialized medical centers. The availability of molecular testing at reasonable costs is mandatory to improve the diagnostic approach to patients with suspected PID. The development of didactic and innovative educational tools has been a critical strategy to improve PID awareness and diagnosis in Peru.
SUMMARY: Developing countries like Peru still have critical limitations to diagnose patients with PIDs such as insufficient awareness in physicians, lack of specialized reference centers, and unavailability of confirmatory genetic testing. Joint work between government, health professionals, patient organizations, and society is essential to overcome these limitations and provide a better future for patients with inborn errors of immunity.

PMID: 33148966 [PubMed – indexed for MEDLINE]

Bloom’s syndrome with growth hormone deficiency: a rare association.

February 17, 2021 By Manish Butte

Bloom’s syndrome with growth hormone deficiency: a rare association.

BMJ Case Rep. 2020 Oct 29;13(10):

Authors: Verpula M, Danda VSR, Paidipally SR, Konda C

Abstract
We report a case of a 5-year-old boy presenting to us with short stature. He was born of consanguineous parentage and was small for gestational age. He had severe short stature, with height Z score of -6.2 SD Score, markedly delayed skeletal age, low level of insulin-like growth factor 1, unstimulated growth hormone and hypoplastic anterior pituitary gland on MRI. He was advised growth hormone (GH) replacement at 2 years of age, but he did not receive it . Later on, he developed photosensitive telangiectatic lesions over face and required multiple hospital admissions for recurrent systemic infections. Genetic analysis confirmed the diagnosis of Bloom’s syndrome. The present case report illustrates the need for high vigilance for conditions like Bloom’s syndrome in growth hormone deficiency (GHD), in whom GH treatment could potentially be harmful. Bloom’s syndrome with GHD is an exceedingly rare association.

PMID: 33122222 [PubMed – indexed for MEDLINE]

Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency.

February 17, 2021 By Manish Butte

Icon for American Society for Clinical Investigation

Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency.

J Clin Invest. 2020 11 02;130(11):5817-5832

Authors: Tan EE, Hopkins RA, Lim CK, Jamuar SS, Ong C, Thoon KC, Koh MJ, Shin EM, Lian DW, Weerasooriya M, Lee CZ, Soetedjo AAP, Lim CS, Au VB, Chua E, Lee HY, Jones LA, James SS, Kaliaperumal N, Kwok J, Tan ES, Thomas B, Wu LX, Ho L, Fairhurst AM, Ginhoux F, Teo AK, Zhang YL, Ong KH, Yu W, Venkatesh B, Tergaonkar V, Reversade B, Chin KC, Tan AM, Liew WK, Connolly JE

Abstract
Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient’s hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.

PMID: 32750042 [PubMed – indexed for MEDLINE]

Disease Severity, Fever, Age, and Sex Correlate With SARS-CoV-2 Neutralizing Antibody Responses.

February 16, 2021 By Manish Butte

Disease Severity, Fever, Age, and Sex Correlate With SARS-CoV-2 Neutralizing Antibody Responses.

Front Immunol. 2020;11:628971

Authors: Schlickeiser S, Schwarz T, Steiner S, Wittke K, Al Besher N, Meyer O, Kalus U, Pruß A, Kurth F, Zoller T, Witzenrath M, Sander LE, Müller MA, Scheibenbogen C, Volk HD, Drosten C, Corman VM, Hanitsch LG

Abstract
Clinical trials on the use of COVID-19 convalescent plasma remain inconclusive. While data on safety is increasingly available, evidence for efficacy is still sparse. Subgroup analyses hint to a dose-response relationship between convalescent plasma neutralizing antibody levels and mortality. In particular, patients with primary and secondary antibody deficiency might benefit from this approach. However, testing of neutralizing antibodies is limited to specialized biosafety level 3 laboratories and is a time- and labor-intense procedure. In this single center study of 206 COVID-19 convalescent patients, clinical data, results of commercially available ELISA testing of SARS-CoV-2 spike-IgG and -IgA, and levels of neutralizing antibodies, determined by plaque reduction neutralization testing (PRNT), were analyzed. At a medium time point of 58 days after symptom onset, only 12.6% of potential plasma donors showed high levels of neutralizing antibodies (PRNT50 ≥ 1:320). Multivariable proportional odds logistic regression analysis revealed need for hospitalization due to COVID-19 (odds ratio 6.87; p-value 0.0004) and fever (odds ratio 3.00; p-value 0.0001) as leading factors affecting levels of SARS-CoV-2 neutralizing antibody titers in convalescent plasma donors. Using penalized estimation, a predictive proportional odds logistic regression model including the most important variables hospitalization, fever, age, sex, and anosmia or dysgeusia was developed. The predictive discrimination for PRNT50 ≥ 1:320 was reasonably good with AUC: 0.86 (with 95% CI: 0.79-0.92). Combining clinical and ELISA-based pre-screening, assessment of neutralizing antibodies could be spared in 75% of potential donors with a maximal loss of 10% of true positives (PRNT50 ≥ 1:320).

PMID: 33584731 [PubMed – in process]

Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency-Features of CT and 18F-FDG Positron Emission Tomography/CT in Clinically Progressive Disease.

February 16, 2021 By Manish Butte

Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency-Features of CT and 18F-FDG Positron Emission Tomography/CT in Clinically Progressive Disease.

Front Immunol. 2020;11:617985

Authors: Fraz MSA, Moe N, Revheim ME, Stavrinou ML, Durheim MT, Nordøy I, Macpherson ME, Aukrust P, Jørgensen SF, Aaløkken TM, Fevang B

Abstract
Common variable immunodeficiency (CVID) is characterized not only by recurrent bacterial infections, but also autoimmune and inflammatory complications including interstitial lung disease (ILD), referred to as granulomatous-lymphocytic interstitial lung disease (GLILD). Some patients with GLILD have waxing and waning radiologic findings, but preserved pulmonary function, while others progress to end-stage respiratory failure. We reviewed 32 patients with radiological features of GLILD from our Norwegian cohort of CVID patients, including four patients with possible monogenic defects. Nineteen had deteriorating lung function over time, and 13 had stable lung function, as determined by pulmonary function testing of forced vital capacity (FVC), and diffusion capacity of carbon monoxide (DLCO). The overall co-existence of other non-infectious complications was high in our cohort, but the prevalence of these was similar in the two groups. Laboratory findings such as immunoglobulin levels and T- and B-cell subpopulations were also similar in the progressive and stable GLILD patients. Thoracic computer tomography (CT) scans were systematically evaluated and scored for radiologic features of GLILD in all pulmonary segments. Pathologic features were seen in all pulmonary segments, with traction bronchiectasis as the most prominent finding. Patients with progressive disease had significantly higher overall score of pathologic features compared to patients with stable disease, most notably traction bronchiectasis and interlobular septal thickening. 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/CT (PET/CT) was performed in 17 (11 with progressive and six with stable clinical disease) of the 32 patients and analyzed by quantitative evaluation. Patients with progressive disease had significantly higher mean standardized uptake value (SUVmean), metabolic lung volume (MLV) and total lung glycolysis (TLG) as compared to patients with stable disease. Nine patients had received treatment with rituximab for GLILD. There was significant improvement in pathologic features on CT-scans after treatment while there was a variable effect on FVC and DLCO.
Conclusion: Patients with progressive GLILD as defined by deteriorating pulmonary function had significantly greater pathology on pulmonary CT and FDG-PET CT scans as compared to patients with stable disease, with traction bronchiectasis and interlobular septal thickening as prominent features.

PMID: 33584710 [PubMed – in process]