Thalassaemias result from mutations of the globin genes that cause reduced or absent haemoglobin production and thus interfere with the critical function of oxygen delivery. They represent the most common single-gene disorders, with 4.83% of the world population carrying globin gene variants. Reduced or absent α-globin (α-thalassaemia) or β-globin (β-thalassaemia) leads to anaemia and multifaceted clinical syndromes. In this second of two reviews on the pathophysiology of haemoglobinopathies, we describe the clinical features, pathophysiology and molecular basis of α- and β-thalassaemias. We then discuss current targeted therapies, including the new oral iron chelators, which, along with chronic transfusions, constitute the mainstay of symptomatic therapy for the majority of patients. Finally, we describe potentially curative therapies, such as bone marrow transplant, and discuss some of the outstanding research studies and questions, including the upcoming field of gene therapy for β-thalassaemia. An accompanying article on haemoglobinopathies (Part I) focuses on sickle cell disease.

The role of cholera toxin and heat-labile enterotoxin in the pathogenesis of diarrhoeal disease has been well documented for many years. In addition to these deleterious effects, a wealth of data is accumulating that suggests that these toxins and their subunits might be used to modulate immune responses in a variety of beneficial ways. In this regard, the toxins can boost immune responses to unrelated antigens, leading to the possibility of their use in the generation of improved vaccines to a variety of pathogens. Furthermore, recent evidence suggests that recombinant preparations of the nontoxic B subunits of the toxins have distinct immunomodulatory activities, with potential applications to the treatment of autoimmune and inflammatory diseases. This article reviews our current understanding of the mechanisms of immune modulation by these fascinating proteins.

The major histocompatibility complex (MHC) harbours genes whose primary function in regulating immune responsiveness to infection is to present foreign antigens to cytotoxic T lymphocytes (CTLs) and T helper cells. In the case of infection by human immunodeficiency virus (HIV), defining the optimal HIV epitopes that are recognised by CTLs is important for vaccine design, and this in turn will depend on the characteristics of the predominant infecting virus. Moreover, the particular MHC human leukocyte antigens (HLAs) expressed by a geographical population is important since these are likely to determine which HIV epitopes are immunodominant in the anti-HIV immune response. Consideration of these aspects has lead to the dawn of a new era of MHC-based vaccine design, in which the CTL epitopes are selected on the basis of the frequency of restricting MHC alleles. This article reviews data on the distribution patterns of molecular subtypes of HLA class I and class II extended haplotypes, discussing distribution among Asian Indians but with reference to global distributions. These data provide a genetic basis for the possible predisposition and fast progression of HIV infections in the Indian population. Since there is selective predominance of different HLA alleles and haplotypes in different populations, a dedicated screening effort is required at the global level to develop MHC-based vaccines against infectious diseases. It is hoped that this might lead to the development of multivalent, poly-epitope, subtype-specific HIV vaccines that are specific for the target geographical location.

Although great advances have been made in the treatment of low- and intermediate-risk neuroblastoma in recent years, the prognosis for advanced disease remains poor. Therapies based on monoclonal antibodies that specifically target tumour cells have shown promise for treatment of high-risk neuroblastoma. This article reviews the use of monoclonal antibodies either as monotherapy or as part of a multifaceted treatment approach for advanced neuroblastoma, and explains how toxins, cytokines, radioactive isotopes or chemotherapeutic drugs can be conjugated to antibodies to enhance their effects. Tumour resistance, the development of blocking antibodies, and other problems hindering the effectiveness of monoclonal antibodies are also discussed. Future therapies under investigation in the area of immunotherapy for neuroblastoma are considered.

Infection with Entamoeba histolytica, the protozoan parasite that causes amoebic colitis and liver abscess, results in 34 million to 50 million symptomatic cases of amoebiasis (all illnesses caused by E. histolytica, including amoebic dysentery) worldwide each year, causing 40 thousand to 100 thousand deaths annually. As a result of accruing biochemical, genetic and immunological data, E. histolytica was re-defined in 1993 to recognise the existence of two morphologically identical but genetically distinct human parasites: E. histolytica, the aetiological agent of invasive intestinal and extraintestinal amoebiasis, and Entamoeba dispar, a non-pathogenic intestinal parasite. Because microscopy is unable to distinguish between these two organisms, it should no longer be relied upon to diagnose amoebiasis. Sensitive and specific molecular techniques that are able to distinguish E. histolytica from E. dispar have been developed recently; they include (1) the detection of an E. histolytica antigen using an enzyme-linked immunosorbent assay (ELISA), (2) the use of the polymerase chain reaction (PCR) to amplify amoebic DNA, and (3) the culture of stool samples followed by isoenzyme analysis. Of these three test methods, only antigen detection using ELISA can be performed rapidly and easily, making it the diagnostic test method of choice for clinical use in the developing world, where the morbidity and mortality caused by E. histolytica are greatest. However, the PCR method is a powerful tool for the genetic typing of different amoebic strains. Together these two methods should result in both improved clinical diagnosis and treatment of amoebiasis, and a greater understanding of the epidemiology of E. histolytica. Such knowledge will not only assist public health efforts to control amoebiasis, but also facilitate the careful testing of the anti-amoebic vaccines that are currently being developed.

The β-thalassaemias are inherited anaemias that form the most common class of monogenic disorders in the world. Treatment options are limited, with allogeneic haematopoietic stem cell transplantation offering the only hope for lifelong cure. However, this option is not available for many patients as a result of either the lack of compatible donors or the increased risk of transplant-related mortality in subjects with organ damage resulting from accumulated iron. The paucity of alternative treatments for patients that fall into either of these categories has led to the development of a revolutionary treatment strategy based on gene therapy. This approach involves replacing allogeneic stem cell transplantation with the transfer of normal globin genes into patient-derived, autologous haematopoietic stem cells. This highly attractive strategy offers several advantages, including bypassing the need for allogeneic donors and the immunosuppression required to achieve engraftment of the transplanted cells and to eliminate the risk of donor-related graft-versus-host disease. This review discusses the many advances that have been made towards this endeavour as well as the hurdles that must still be overcome before gene therapy for β-thalassaemia, as well as many other gene therapy applications, can be widely applied in the clinic.

Fever-associated seizures or epilepsy (FASE) is primarily characterised by the occurrence of a seizure or epilepsy usually accompanied by a fever. It is common in infants and children, and generally includes febrile seizures (FS), febrile seizures plus (FS+), Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFSP). The aetiology of FASE is unclear. Genetic factors may play crucial roles in FASE. Mutations in certain genes may cause a wide spectrum of phenotypical overlap ranging from isolated FS, FS+ and GEFSP to DS. Synapse-associated proteins, postsynaptic GABAA receptor, and sodium channels play important roles in synaptic transmission. Mutations in these genes may involve in the pathogenesis of FASE. Elevated temperature promotes synaptic vesicle (SV) recycling and enlarges SV size, which may enhance synaptic transmission and contribute to FASE occurring. This review provides an overview of the loci, genes, underlying pathogenesis and the fever-inducing effect of FASE. It may provide a more comprehensive understanding of pathogenesis and contribute to the clinical diagnosis of FASE.

Alveolar macrophages (AMs) are lung-resident myeloid cells that sit at the interface of the airway and lung tissue. Under homeostatic conditions, their primary function is to clear debris, dead cells and excess surfactant from the airways. They also serve as innate pulmonary sentinels for respiratory pathogens and environmental airborne particles and as regulators of pulmonary inflammation. However, they have not typically been viewed as primary therapeutic targets for respiratory diseases. Here, we discuss the role of AMs in various lung diseases, explore the potential therapeutic strategies to target these innate cells and weigh the potential risks and challenges of such therapies. Additionally, in the context of the COVID-19 pandemic, we examine the role AMs play in severe disease and the therapeutic strategies that have been harnessed to modulate their function and protect against severe lung damage. There are many novel approaches in development to target AMs, such as inhaled antibiotics, liposomal and microparticle delivery systems, and host-directed therapies, which have the potential to provide critical treatment to patients suffering from severe respiratory diseases, yet there is still much work to be done to fully understand the possible benefits and risks of such approaches.

Coronavirus disease 2019 (COVID-19) is associated with autoimmunity and systemic inflammation. Patients with autoimmune rheumatic and musculoskeletal disease (RMD) may be at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, based on evidence from the literature, as well as international scientific recommendations, we review the relationships between COVID-19, autoimmunity and patients with autoimmune RMDs, as well as the basics of a multisystemic inflammatory syndrome associated with COVID-19. We discuss the repurposing of pharmaceutics used to treat RMDs, the principles for the treatment of patients with autoimmune RMDs during the pandemic and the main aspects of vaccination against SARS-CoV-2 in autoimmune RMD patients.

Ischaemic heart disease and stroke are vascular events with serious health consequences worldwide. Recent genetic and epigenetic techniques have revealed many genetic determinants of these vascular events and simplified the approaches to research focused on ischaemic heart disease and stroke. The pathogenetic mechanisms of ischaemic heart disease and stroke are complex, with mitochondrial involvement (partially or entirely) recently gaining substantial support. Not only can mitochondrial reactive oxygen species give rise to ischaemic heart disease and stroke by production of oxidised low-density lipoprotein and induction of apoptosis, but the impact on pericytes contributes directly to the pathogenesis. Over the past two decades, publications implicate the causative role of nuclear genes in the development of ischaemic heart disease and stroke, in contrast to the potential role of mitochondrial DNA (mtDNA) in the pathophysiology of the disorders, which is much less understood, although recent studies do demonstrate that the involvement of mitochondria and mtDNA in the development of ischaemic heart disease and stroke is likely to be larger than originally thought, with the novel discovery of links among mitochondria, mtDNA and vascular events. Here we explore the molecular events and mtDNA alterations in relation to the role of mitochondria in ischaemic heart disease and stroke.

The trafficking and processing steps that occur in cells that are infected with influenza virus play a crucial role in the outcome of infection. These steps are targets for new and future anti-viral drugs, and can affect the relative virulence of the virus and its ability to cause disease. The virus first binds to its host cell via specific sialic acid residues, which can control the species tropism of the virus. The internalisation of the virus, into the nucleus of the cell, is dependent on a low pH, and this process is therapeutically targeted by the drug amantadine. Following replication, the newly formed viral genomes leave the nucleus and assemble into infectious particles at the plasma membrane. The targeting and processing of the various viral components at this late stage of the infectious cycle can have a major effect on the ability of the virus to spread and cause disease in its host. Finally, the release of viruses is dependent on the enzyme neuraminidase (NA), and this function has recently been targeted by the NA inhibitors, a new generation of drugs against influenza virus.

Genetic characterization of individuals at risk of Alzheimer's disease (AD), i.e. people having amyloid deposits in the brain without symptoms, people suffering from subjective cognitive decline (SCD) or mild cognitive impairment (MCI), has spurred the interests of researchers. However, their pre-dementia genetic profile remains mostly unexplored. In this study, we reviewed the loci related to phenotypes of AD, MCI and SCD from literature and performed the first meta-analyses evaluating the role of apolipoprotein E (APOE) in the risk of conversion from a healthy status to MCI and SCD. For AD dementia risk, an increased number of loci have been identified; to date, 28 genes have been associated with Late Onset AD. In MCI syndrome, APOE is confirmed as a pheno-conversion factor leading from MCI to AD, and clusterin is a promising candidate. Additionally, our meta-analyses revealed APOE as genetic risk factor to convert from a healthy status to MCI [OR = 1.849 (1.587–2.153); P = 2.80  × 10−15] and to a lesser extent from healthy status to SCD [OR = 1.151 (1.015–1.304); P = 0.028]. Thus, we believe that genetic studies in longitudinal SCD and MCI series may provide new therapeutic targets and improve the existing knowledge of AD. This type of studies must be completed on healthy subjects to better understand the natural disease resistance to brain insults and neurodegeneration.

The central nervous system (CNS), consisting of the brain and spinal cord, regulates the mind and functions of the organs. CNS diseases, leading to changes in neurological functions in corresponding sites and causing long-term disability, represent one of the major public health issues with significant clinical and economic burdens worldwide. In particular, the abnormal changes in the extracellular matrix under various disease conditions have been demonstrated as one of the main factors that can alter normal cell function and reduce the neuroregeneration potential in damaged tissue. Decellularised extracellular matrix (dECM)-based biomaterials have been recently utilised for CNS applications, closely mimicking the native tissue. dECM retains tissue-specific components, including proteoglycan as well as structural and functional proteins. Due to their unique composition, these biomaterials can stimulate sensitive repair mechanisms associated with CNS damages. Herein, we discuss the decellularisation of the brain and spinal cord as well as recellularisation of acellular matrix and the recent progress in the utilisation of brain and spinal cord dECM.

All species of the order Chlamydiales are obligate intracellular eubacterial pathogens of their various hosts. Two chlamydial species, Chlamydia trachomatis and Chlamydia pneumoniae, are primarily human pathogens, and each is known to cause important diseases. Some strains of C. trachomatis are sexually transmitted and frequently cause severe reproductive problems, primarily in women. Other strains of the organism serve as the aetiological agents for blinding trachoma, still the leading cause of preventable blindness in underdeveloped nations. C. pneumoniae is a respiratory pathogen known to cause community-acquired pneumonia. Importantly, both organisms engender an immunopathogenic response in the human host, and both have been associated with widely diverse, relatively common and currently idiopathic chronic diseases, most of which include an important autoimmune component. In this article, we explore the available experimental data regarding the possible elicitation of autoimmunity in various contexts by chlamydial infection, and we suggest several avenues for research to explore this potentially important issue further.

Invariant natural killer T (iNKT) cells are innate lymphocytes whose functions are regulated by self and foreign glycolipid antigens presented by the antigen-presenting molecule CD1d. Activation of iNKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers and self-antigens. The nature of CD1d-restricted antigens, the manner in which they are recognised and the unique effector functions of iNKT cells suggest an innate immunoregulatory role for this subset of T cells. Their ability to respond fast and our ability to steer iNKT cell cytokine response to altered lipid antigens make them an important target for vaccine design and immunotherapies against autoimmune diseases. This review summarises our current understanding of CD1d-restricted antigen presentation, the recognition of such antigens by an invariant T-cell receptor on iNKT cells, and the functional consequences of these interactions.

Human papillomavirus 16 (HPV16) infection is the aetiologic factor for the development of cervical dysplasia and is regarded as highly carcinogen, because it is implicated in more than 50% of cervical cancer cases, worldwide. The tumourigenic potential of HPV16 has triggered the extensive sequence analysis of viral genome in order to identify nucleotide variations and amino acid substitutions that influence viral oncogenicity and subsequently the initiation and progression of cervical cancer. Nowadays, specific mutations of HPV16 DNA have been associated with an increased risk of high-grade squamous intraepithelial lesions and invasive cervical cancer (ICC) development, including E6: Q14H, H78Y, L83V, Ε7: N29S, S63F, E2: H35Q, P219S, T310K, E5: I65V, whereas highly conserved regions of viral DNA have been extensively characterised. In addition, numerous novel HPV16 mutations are observed among the studied populations from various geographic regions, hence advocating that different HPV16 strains seem to emerge with different tumourigenic capacities. The present review focuses on the variability of the early genes and the long control region, emphasising on the association of specific mutations with the development of severe dysplasia. Finally, it evaluates whether specific regions of HPV16 DNA are able to serve as valuable biomarkers for cervical cancer risk.

Memory is the process by which organisms are able to record their experiences, and use this information to adapt their responses to the environment. As such, it is vital for survival. In recent years, the development of spatially and temporally selective techniques for the regulation of gene expression has allowed the molecular details of this process to emerge. Here we review the molecular mechanisms thought to underlie memory acquisition and storage, as well as discuss recent evidence regarding the mechanisms of subsequent memory consolidation.

Cellular immune therapy for severe autoimmune diseases can now be considered when such patients are refractory to conventional treatment. The use of autologous stem cell transplantation (ASCT) to treat human autoimmune diseases has been initiated following promising results in a variety of animal models. Anecdotal observations have been made of autoimmune disease remission in patients who have undergone allogeneic bone marrow transplantation as a result of coincidental haematological malignancies. The possibility of inducing immunological self-tolerance by ASCT is particularly attractive as a means for treating juvenile idiopathic arthritis (JIA). In this disease, ASCT restores self-tolerance both through a cell-intrinsic mechanism, involving the reprogramming of autoreactive T cells, and through a cell-extrinsic mechanism, involving a renewal of the immune balance between CD4+CD25+ regulatory T cells and other T cells. This review describes the clinical results of ASCT performed for this disease and the possible underlying immunological mechanisms.

Resistance to anti-cancer drugs (drug resistance) can be defined in the laboratory by the amount of anti-cancer drug that is required to produce a given level of cell death (drug response). Clinical drug resistance can be defined either as a lack of reduction of the size of a tumour following chemotherapy or as the occurrence of clinical relapse after an initial ‘positive’ response to anti-tumour treatment. Many studies of tumour samples do not directly measure drug resistance in the laboratory (because it is difficult to perform functional assays on tumour tissue); instead, key proteins or genes that are involved in particular mechanisms of drug resistance have been proposed as ‘markers’ of drug resistance. In this review, we have focused on the problems that can arise when attempts are made to relate the relevance of laboratory-identified molecular mechanisms of drug resistance to anti-cancer drug resistance that occurs in patients.

Prostate cancer is one of the leading causes of cancer-related death in the USA. In the past decade, tremendous progress has been made in the identification and understanding of the genetic factors related to prostate cancer development. Unlike many other types of cancers, only a small fraction of prostate cancer cases are aggressive and life-threatening. The factors related to prostate cancer development and progression appear complex and diverse. This review summarises some of the important findings in the areas of genome and gene expression abnormalities in prostate cancer, and aims to provide a comprehensive view of new developments in these areas.